chr2-73451886-A-G

Variant names:

• chr2-73451886-A-G
• rs45608038
• NM_001378454.1:c.5359A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.5359A>G​(p.Asn1787Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,611,588 control chromosomes in the GnomAD database, including 259 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1787K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 32)
  • Exomes 𝑓: 0.015 (232 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.59
• Publications: 11 publications found

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002682358).
• BP6: Variant 2-73451886-A-G is Benign according to our data. Variant chr2-73451886-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0145 (2173/149794) while in subpopulation SAS AF = 0.0191 (89/4668). AF 95% confidence interval is 0.0172. There are 27 homozygotes in GnomAd4. There are 1136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.5359A>G	p.Asn1787Asp	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.5359A>G	p.Asn1787Asp	missense	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.5359A>G	p.Asn1787Asp	missense	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.5233A>G	p.Asn1745Asp	missense	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000423048.5	TSL:1	n.190A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2173 AN: 149672 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.0410

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0175

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0117

GnomAD2 exomes AF: 0.0147 AC: 3665 AN: 248994 AF XY: 0.0157

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00675

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0155 AC: 22642 AN: 1461794 Hom.: 232 Cov.: 39 AF XY: 0.0158 AC XY: 11486 AN XY: 727196

African (AFR) AF: 0.00251 AC: 84 AN: 33470

American (AMR) AF: 0.00693 AC: 310 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 474 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0158 AC: 1360 AN: 86254

European-Finnish (FIN) AF: 0.0352 AC: 1882 AN: 53418

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17641 AN: 1111950

Other (OTH) AF: 0.0134 AC: 812 AN: 60386

GnomAD4 genome AF: 0.0145 AC: 2173 AN: 149794 Hom.: 27 Cov.: 32 AF XY: 0.0155 AC XY: 1136 AN XY: 73250

African (AFR) AF: 0.00282 AC: 115 AN: 40728

American (AMR) AF: 0.0147 AC: 223 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 66 AN: 3428

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4912

South Asian (SAS) AF: 0.0191 AC: 89 AN: 4668

European-Finnish (FIN) AF: 0.0386 AC: 405 AN: 10492

Middle Eastern (MID) AF: 0.0150 AC: 4 AN: 266

European-Non Finnish (NFE) AF: 0.0180 AC: 1209 AN: 67186

Other (OTH) AF: 0.0116 AC: 24 AN: 2076

Alfa AF: 0.0151 Hom.: 68

Bravo AF: 0.0113

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00243 AC: 9

ESP6500EA AF: 0.0163 AC: 134

ExAC AF: 0.0144 AC: 1738

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 13, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn1786Asp in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 3.54% (234/6614) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45608038).

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALMS1: BP4, BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Alstrom syndrome Benign:3

Sep 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Monogenic diabetes Benign:1

Oct 26, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BP4 (REVEL =0.006 + 9 predictors), BA1 (1.5% MAF in gnomAD, 3.5 % in gnomAD European Finnish population), BS2 (60 homozygotes in gnomAD)= benign

Cardiovascular phenotype Benign:1

Jan 09, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0010
DANN	Benign	0.33
DEOGEN2	Benign	0.011	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.0027	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.6
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.32	T
Vest4		0.044
ClinPred		0.0011	T
GERP RS		-9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.028
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45608038; hg19: chr2-73679013; COSMIC: COSV52501641; COSMIC: COSV52501641;