chr2-73453080-C-T

Position:

• chr2-73453080-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.6553C>T​(p.Pro2185Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,006 control chromosomes in the GnomAD database, including 48 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (29 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (19 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.561

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002175182).
• BP6: Variant 2-73453080-C-T is Benign according to our data. Variant chr2-73453080-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00992 (1510/152290) while in subpopulation AFR AF= 0.0341 (1417/41574). AF 95% confidence interval is 0.0326. There are 29 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.6553C>T	p.Pro2185Ser	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.6556C>T	p.Pro2186Ser	missense_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.6553C>T	p.Pro2185Ser	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes AF: 0.00990 AC: 1507 AN: 152172 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00252 AC: 626 AN: 248690 Hom.: 12 AF XY: 0.00197 AC XY: 266 AN XY: 134890

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.000955 AC: 1396 AN: 1461716 Hom.: 19 Cov.: 37 AF XY: 0.000855 AC XY: 622 AN XY: 727140

Gnomad4 AFR exome AF: 0.0327

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00992 AC: 1510 AN: 152290 Hom.: 29 Cov.: 32 AF XY: 0.00960 AC XY: 715 AN XY: 74472

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00176 Hom.: 11

Bravo AF: 0.0112

ESP6500AA AF: 0.0321 AC: 120

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00295 AC: 356

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2016	Variant summary: ALMS1 c.6550C>T (alternative name c.6556C>T) variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 4/5 in-silico tools predict this variant to be benign, but these in silico predictions have not been confirmed with functional studies. This variant is found in 355/120368 control chromosomes (6 homozygotes) at a frequency of 0.0029493, with the highest frequency in Africans (0.03312; 5 homozygotes). This African allele frequency significantly exceeds maximal expected frequency of a pathogenic allele (0.0022361), suggesting that this is a benign polymorphism in Africans. Mutations in the ALMS1 gene have been reported with autosomal recessive Alstrom disease (AS), which has estimated prevalence of 1/600,000. 60% of patients with Alstrom syndrome have Dilated Cardiomyopathy (DCM) among other presenting features such as obesity, retinal rod cone dystrophy, diabetes, and progressive hearing loss. This gene was included in Cardio Gene Screening panel based upon the reported findings of DCM in patients with AS. Mutations in ALMS1 gene have not been implicated in isolated cases of cardiomyopathy, which has higher prevalence (1/500), than the AS alone. Taken together, this is probably a normal variant and was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro2184Ser in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 3.31% (323/9752) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs77555300). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Alstrom syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	- -
Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs77555300 in Alstrom syndrome yet. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 15, 2019

ACMG criteria: BP1 (missense when truncating are ds causing), BA1 (3.4% MAF in gnomAD Africans), BS2 (18 homozygotes in gnomAD), BP4 (REVEL 0.028 + 8 predictors)= Benign (ALMS1 p.P2184S and p.K1810N are likely in LD) -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.069
DANN	Benign	0.52
DEOGEN2	Benign	0.032	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.35	T;T;T
Vest4		0.062
MVP		0.067
ClinPred		0.0012	T
GERP RS		-5.6
Varity_R		0.016
gMVP		0.068

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: rs77555300; hg19: chr2-73680207;