chr2-73449188-A-G

Position:

• chr2-73449188-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378454.1(ALMS1):​c.2661A>G​(p.Val887=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,014 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (16 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.664

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-73449188-A-G is Benign according to our data. Variant chr2-73449188-A-G is described in ClinVar as [Benign]. Clinvar id is 240990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00745 (1133/152182) while in subpopulation AFR AF= 0.0251 (1040/41512). AF 95% confidence interval is 0.0238. There are 11 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.2661A>G	p.Val887=	synonymous_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.2664A>G	p.Val888=	synonymous_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.2661A>G	p.Val887=	synonymous_variant	8/23	1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1136 AN: 152064 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00214 AC: 534 AN: 249034 Hom.: 8 AF XY: 0.00170 AC XY: 230 AN XY: 135078

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000870 AC: 1272 AN: 1461832 Hom.: 16 Cov.: 40 AF XY: 0.000733 AC XY: 533 AN XY: 727224

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00745 AC: 1133 AN: 152182 Hom.: 11 Cov.: 33 AF XY: 0.00732 AC XY: 545 AN XY: 74404

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00400 Hom.: 3

Bravo AF: 0.00808

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Val886Val in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 2.78% (272/9778) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs76266696). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2016	Variant summary: The ALMS1 c.2658A>G (p.Val886Val, alternative name c.2664A>G) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict a creation of cryptic donor site. This silent variant is 100 nucleotides away from the exon-intron bounday; thus it is unlikely that the cryptic site will be used. In addition, these predictions have yet to be confirmed by functional studies. This variant was found in 310/120600 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0278175 (272/9778). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. Taken together, this variant is classified as a benign variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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. -

Alstrom syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.37
DANN	Benign	0.51

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

Other links and lift over

dbSNP: rs76266696; hg19: chr2-73676315;