chr2-73452739-T-C

Position:

chr2-73452739-T-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.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. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1600 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19561 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.124

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=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	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.6212T>C	p.Ile2071Thr	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.6212T>C	p.Ile2071Thr	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.6212T>C	p.Ile2071Thr	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20924

AN:

152070

Hom.:

1599

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.161

AC XY:

117148

AN XY:

726836

show subpopulations

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.:

AF XY:

0.135

AC XY:

10074

AN XY:

74412

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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). -

Alstrom syndrome

Benign:3

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

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

0.14

BayesDel_addAF

Benign

-0.69

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

LIST_S2

Benign

0.53

T;T;T

MetaRNN

Benign

0.00094

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.40

Sift4G

Benign

1.0

T;T;T

Vest4

0.048

ClinPred

0.0012

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

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