16-21278244-C-A

Position:

chr16-21278244-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001376256.1(CRYM):c.8G>T(p.Arg3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,584,580 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

CRYM
NM_001376256.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.107

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043696165).

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1 linkuse as main transcript	c.8G>T	p.Arg3Leu	missense_variant	1/8	ENST00000572914.2
CRYM	NM_001888.5 linkuse as main transcript	c.8G>T	p.Arg3Leu	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2 linkuse as main transcript	c.8G>T	p.Arg3Leu	missense_variant	1/8	2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000184

AC:

AN:

206782

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

111970

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00116

Gnomad SAS exome

AF:

0.000573

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.000103

AC:

148

AN:

1432272

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

710568

show subpopulations

Gnomad4 AFR exome

AF:

0.000153

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000662

Gnomad4 SAS exome

AF:

0.000876

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.000707

GnomAD4 genome

AF:

0.000223

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000416

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 21, 2023	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3 of the CRYM protein (p.Arg3Leu). ClinVar contains an entry for this variant (Variation ID: 289303). This variant has not been reported in the literature in individuals affected with CRYM-related conditions. This variant is present in population databases (rs149797560, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.30

T;T;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.013

M_CAP

Benign

0.048

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

N;N;.;.

REVEL

Benign

0.17

Sift

Benign

0.26

T;T;.;.

Sift4G

Benign

0.29

T;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.091

MVP

0.57

MPC

0.40

ClinPred

0.026

GERP RS

1.5

Varity_R

0.32

gMVP

0.74

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