2-73490794-C-G

Position:

chr2-73490794-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.8835C>G(p.Asn2945Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,052 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 5 hom., cov: 32)

Exomes 𝑓: 0.012 ( 154 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.661

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038140416).

BP6

Variant 2-73490794-C-G is Benign according to our data. Variant chr2-73490794-C-G is described in ClinVar as [Benign]. Clinvar id is 221010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00793 (1208/152280) while in subpopulation NFE AF= 0.0129 (875/68022). AF 95% confidence interval is 0.0122. There are 5 homozygotes in gnomad4. There are 538 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.8835C>G	p.Asn2945Lys	missense_variant	10/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.8835C>G	p.Asn2945Lys	missense_variant	10/23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.8835C>G	p.Asn2945Lys	missense_variant	10/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00796

AC:

1211

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.00924

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00876

AC:

2185

AN:

249400

Hom.:

AF XY:

0.00895

AC XY:

1211

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.00735

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00592

Gnomad FIN exome

AF:

0.00844

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.00760

GnomAD4 exome

AF:

0.0123

AC:

17945

AN:

1461772

Hom.:

154

Cov.:

AF XY:

0.0122

AC XY:

8849

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.00628

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00546

Gnomad4 FIN exome

AF:

0.00955

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.00798

GnomAD4 genome

AF:

0.00793

AC:

1208

AN:

152280

Hom.:

Cov.:

AF XY:

0.00722

AC XY:

538

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00924

Gnomad4 NFE

AF:

0.0129

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00711

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00372

AC:

ESP6500EA

AF:

0.0144

AC:

118

ExAC

AF:

0.00963

AC:

1164

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ALMS1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2018	This variant is associated with the following publications: (PMID: 16720663, 25296579, 17594715) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asn2944Lys in exon 10 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 1.38% (921/66738) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs35062203). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Alstrom syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 22, 2019

ACMG criteria: BP4 (9 predictors; Revel score 0.007), BS2 (18 homozygotes in gnomAD), BP1 (missense in gene with truncating mutations), BA1 (1.4% in European gnomAD; 1.1% in ESP); [InVitae, Partners & Childrens Mercy say benign but no longer using BP6]= benign -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 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

0.15

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.89

DANN

Benign

0.73

DEOGEN2

Benign

0.028

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.35

Sift4G

Benign

0.25

T;T;T

Vest4

0.11

MVP

0.072

ClinPred

0.000034

GERP RS

-0.22

Varity_R

0.025

gMVP

0.0077

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over