Variant 16-21258783-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_001376256.1(CRYM):c.943T>C(p.Ter315GlnextTer5) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000335 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CRYM
NM_001376256.1 stop_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00

Variant links:

Genes affected

CRYM (HGNC:2418): (crystallin mu) Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles. Mutations in this gene have been associated with autosomal dominant non-syndromic deafness. [provided by RefSeq, Sep 2014]

CRYM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Stoplost variant in NM_001376256.1 Downstream stopcodon found after 32 codons.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYM	NM_001376256.1 linkuse as main transcript	c.943T>C	p.Ter315GlnextTer5	stop_lost	8/8	ENST00000572914.2	NP_001363185.1
CRYM	NM_001888.5 linkuse as main transcript	c.943T>C	p.Ter315GlnextTer5	stop_lost	10/10		NP_001879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYM	ENST00000572914.2 linkuse as main transcript	c.943T>C	p.Ter315GlnextTer5	stop_lost	8/8	2	NM_001376256.1	ENSP00000461904	P1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251206

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000197

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000721

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000504

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 40

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 26, 2019

The inherited c.943T>C (p.Ter315GlnextTer5) variant identified in the CRYM gene is a stop loss which substitutes the stop codon (amino acid 315/315; coding exon 10/10) for a Glutamine, which is predicted to extend the protein by 5 C-terminal amino acids. This variant is found with low frequency in gnomAD (22 heterozygotes, 0 homozygotes; allele frequency: 7.79e-5) and ExAC (12 heterozygotes, 0 homozygotes; allele frequency: 9.89e-5), suggesting it is not a common benign variant in the populations represented in these databases. This variant is absent from ClinVar, however a different amino acid change at the same amino acid (c.945A>T; p.Ter315TyrextTer5) has been reported as pathogenic (VarID:16934). While the p.Ter315GlnextTer5 identified here has not been reported in affected individuals in the literature, the p.Ter315TyrextTer5 variant reported in ClinVar has been identified as a de novo variant in an individual with bilateral moderate sensorineural hearing loss affecting all frequencies [PMID: 12471561], and in vitro functional studies suggested this variant may lead to mislocalization of the CRYM protein to the cytoplasm [PMID: 16740909]. While studies supporting the pathogenicity of the p.Ter315TyrextTer5 variant are promising, the lack of affected individuals reported or functional evidence supporting the pathogenicity of the c.943T>C (p.Ter315GlnextTer5) variant identified here leads to its classification as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.81

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

N;N;N;N

Vest4

0.14

GERP RS

5.5

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