chr2-73489976-G-C

Position:

chr2-73489976-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.8017G>C(p.Asp2673His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,614,018 control chromosomes in the GnomAD database, including 16,532 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 0.13 ( 1388 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15144 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0780

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:

ALMS1 (HGNC:):

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=0.0012926459).

BP6

Variant 2-73489976-G-C is Benign according to our data. Variant chr2-73489976-G-C is described in ClinVar as [Benign]. Clinvar id is 383775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.8017G>C	p.Asp2673His	missense_variant	10/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.8017G>C	p.Asp2673His	missense_variant	10/23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.8017G>C	p.Asp2673His	missense_variant	10/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20079

AN:

152086

Hom.:

1389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0908

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.177

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.138

AC:

34310

AN:

249522

Hom.:

2602

AF XY:

0.142

AC XY:

19236

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.0558

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.216

Gnomad SAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.141

AC:

205812

AN:

1461814

Hom.:

15144

Cov.:

AF XY:

0.142

AC XY:

103476

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.0591

Gnomad4 ASJ exome

AF:

0.151

Gnomad4 EAS exome

AF:

0.241

Gnomad4 SAS exome

AF:

0.169

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.137

GnomAD4 genome

AF:

0.132

AC:

20086

AN:

152204

Hom.:

1388

Cov.:

AF XY:

0.132

AC XY:

9831

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.0907

Gnomad4 ASJ

AF:

0.153

Gnomad4 EAS

AF:

0.222

Gnomad4 SAS

AF:

0.176

Gnomad4 FIN

AF:

0.149

Gnomad4 NFE

AF:

0.135

Gnomad4 OTH

AF:

0.133

Alfa

AF:

0.114

Hom.:

371

Bravo

AF:

0.127

TwinsUK

AF:

0.145

AC:

536

ALSPAC

AF:

0.141

AC:

543

ESP6500AA

AF:

0.121

AC:

451

ESP6500EA

AF:

0.132

AC:

1081

ExAC

AF:

0.141

AC:

17022

Asia WGS

AF:

0.187

AC:

649

AN:

3478

EpiCase

AF:

0.134

EpiControl

AF:

0.134

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Benign:3

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

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asp2672His in exon 10 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 21.84% (1884/8626) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs2017116). -
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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

4.9

DANN

Benign

0.65

DEOGEN2

Benign

0.0064

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.21

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.24

Sift4G

Benign

0.85

T;T;T

Vest4

0.043

ClinPred

0.000014

GERP RS

2.6

Varity_R

0.039

gMVP

0.13

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