2-73453381-G-C

Position:

chr2-73453381-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.6854G>C(p.Arg2285Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,278 control chromosomes in the GnomAD database, including 66,720 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 0.39 ( 15845 hom., cov: 31)

Exomes 𝑓: 0.24 ( 50875 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.13

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=1.2201531E-6).

BP6

Variant 2-73453381-G-C is Benign according to our data. Variant chr2-73453381-G-C is described in ClinVar as [Benign]. Clinvar id is 383760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 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.6854G>C	p.Arg2285Pro	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.6854G>C	p.Arg2285Pro	missense_variant	8/23		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.6854G>C	p.Arg2285Pro	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58584

AN:

151550

Hom.:

15782

Cov.:

show subpopulations

Gnomad AFR

AF:

0.768

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.341

GnomAD3 exomes

AF:

0.267

AC:

66335

AN:

248434

Hom.:

12241

AF XY:

0.249

AC XY:

33598

AN XY:

134794

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.408

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.00607

Gnomad SAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

AF:

0.244

AC:

356869

AN:

1461610

Hom.:

50875

Cov.:

AF XY:

0.240

AC XY:

174511

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.781

Gnomad4 AMR exome

AF:

0.408

Gnomad4 ASJ exome

AF:

0.204

Gnomad4 EAS exome

AF:

0.0122

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.232

Gnomad4 NFE exome

AF:

0.237

Gnomad4 OTH exome

AF:

0.251

GnomAD4 genome

AF:

0.387

AC:

58711

AN:

151668

Hom.:

15845

Cov.:

AF XY:

0.380

AC XY:

28163

AN XY:

74074

show subpopulations

Gnomad4 AFR

AF:

0.768

Gnomad4 AMR

AF:

0.373

Gnomad4 ASJ

AF:

0.205

Gnomad4 EAS

AF:

0.00715

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.242

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.337

Alfa

AF:

0.222

Hom.:

3112

Bravo

AF:

0.416

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.234

AC:

901

ESP6500AA

AF:

0.742

AC:

2723

ESP6500EA

AF:

0.239

AC:

1952

ExAC

AF:

0.269

AC:

32512

Asia WGS

AF:

0.124

AC:

432

AN:

3476

EpiCase

AF:

0.232

EpiControl

AF:

0.237

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 01, 2021	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg2284Pro in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 87.82% (1161/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6546839). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

0.053

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.0072

T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.36

Sift4G

Benign

1.0

T;T;T

Vest4

0.064

ClinPred

0.013

GERP RS

5.5

Varity_R

0.19

gMVP

0.22

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