rs10496192

chr2-73452739-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):c.6212T>C(p.Ile2071Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,212 control chromosomes in the GnomAD database, including 21,161 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2071V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1600 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19561 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.124

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.441972E-4).
• BP6: Variant 2-73452739-T-C is Benign according to our data. Variant chr2-73452739-T-C is described in ClinVar as [Benign]. Clinvar id is 383769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.6212T>C	p.Ile2071Thr	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.6215T>C	p.Ile2072Thr	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.6212T>C	p.Ile2071Thr	missense_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20924 AN: 152070 Hom.: 1599 Cov.: 32

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.145 AC: 35804 AN: 246918 Hom.: 2864 AF XY: 0.147 AC XY: 19725 AN XY: 134302

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00413

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.161 AC: 234698 AN: 1461024 Hom.: 19561 Cov.: 38 AF XY: 0.161 AC XY: 117148 AN XY: 726836

Gnomad4 AFR exome AF: 0.0794

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.00403

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.138 AC: 20938 AN: 152188 Hom.: 1600 Cov.: 32 AF XY: 0.135 AC XY: 10074 AN XY: 74412

Gnomad4 AFR AF: 0.0810

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.154

Alfa AF: 0.159 Hom.: 3484

Bravo AF: 0.140

TwinsUK AF: 0.164 AC: 609

ALSPAC AF: 0.168 AC: 649

ESP6500AA AF: 0.0804 AC: 292

ESP6500EA AF: 0.167 AC: 1356

ExAC AF: 0.142 AC: 17109

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.177

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ile2070Thr in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 16.61% (10786/64944) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs10496192). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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. -

Alstrom syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

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	Benign	0.14
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	1.4
Dann	Benign	0.56
DEOGEN2	Benign	0.023	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.00094	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
Sift4G	Benign	1.0	T;T;T
Vest4		0.048
ClinPred		0.0012	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.018

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: rs10496192; hg19: chr2-73679866;