2-73451960-G-C

Position:

• chr2-73451960-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378454.1(ALMS1):​c.5433G>C​(p.Lys1811Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,584 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0099 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (18 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.160

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024687946).
• BP6: Variant 2-73451960-G-C is Benign according to our data. Variant chr2-73451960-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241002.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00986 (1499/151982) while in subpopulation AFR AF= 0.034 (1411/41452). AF 95% confidence interval is 0.0326. There are 27 homozygotes in gnomad4. There are 710 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.5433G>C	p.Lys1811Asn	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.5436G>C	p.Lys1812Asn	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.5433G>C	p.Lys1811Asn	missense_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1496 AN: 151864 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00244 AC: 609 AN: 249118 Hom.: 11 AF XY: 0.00186 AC XY: 252 AN XY: 135194

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000927 AC: 1355 AN: 1461602 Hom.: 18 Cov.: 38 AF XY: 0.000805 AC XY: 585 AN XY: 727106

Gnomad4 AFR exome AF: 0.0327

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00986 AC: 1499 AN: 151982 Hom.: 27 Cov.: 32 AF XY: 0.00955 AC XY: 710 AN XY: 74318

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.000689 Hom.: 3

Bravo AF: 0.0111

ESP6500AA AF: 0.0324 AC: 120

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00288 AC: 348

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs78039319 in Alstrom syndrome yet. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys1810Asn in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 3.30% (320/9702) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs78039319). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2016	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. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 15, 2019

ACMG criteria: BP4 (REVEL 0.049 + 6 predictors; not using PP3 (2 predictors)), BP1 (missense when truncating cause ds), BS2 (18 homozygotes in gnomAD), BA1 (3.4% MAF in gnomAD African): Benign ( ALMS1 p.P2184S and p.K1810N are likely in LD) -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.22	T;T;T
Vest4		0.15
MVP		0.061
ClinPred		0.0091	T
GERP RS		-1.8
Varity_R		0.031
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs78039319; hg19: chr2-73679087;