2-73489976-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/17 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. D2673E) has been classified as Uncertain significance.

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

Publications

26 publications found

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 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

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.8017G>C	p.Asp2673His	missense_variant	Exon 10 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.8017G>C	p.Asp2673His	missense_variant	Exon 10 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.8017G>C	p.Asp2673His	missense_variant	Exon 10 of 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

GnomAD2 exomes

AF:

0.138

AC:

34310

AN:

249522

AF XY:

0.142

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 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

African (AFR)

AF:

0.129

AC:

4307

AN:

33480

American (AMR)

AF:

0.0591

AC:

2641

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3959

AN:

26136

East Asian (EAS)

AF:

0.241

AC:

9573

AN:

39700

South Asian (SAS)

AF:

0.169

AC:

14580

AN:

86258

European-Finnish (FIN)

AF:

0.154

AC:

8251

AN:

53410

Middle Eastern (MID)

AF:

0.153

AC:

882

AN:

5768

European-Non Finnish (NFE)

AF:

0.138

AC:

153327

AN:

1111942

Other (OTH)

AF:

0.137

AC:

8292

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

12080

24161

36241

48322

60402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5590

11180

16770

22360

27950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.132

AC:

20086

AN:

152204

Hom.:

1388

Cov.:

AF XY:

0.132

AC XY:

9831

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.121

AC:

5036

AN:

41542

American (AMR)

AF:

0.0907

AC:

1386

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

531

AN:

3470

East Asian (EAS)

AF:

0.222

AC:

1152

AN:

5180

South Asian (SAS)

AF:

0.176

AC:

848

AN:

4822

European-Finnish (FIN)

AF:

0.149

AC:

1571

AN:

10570

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9200

AN:

68012

Other (OTH)

AF:

0.133

AC:

281

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

896

1792

2688

3584

4480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Sep 23, 2016

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. -

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.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). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

4.9

(source)

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

PhyloP100

0.078

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over