16-21278144-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001376256.1(CRYM):c.108C>A(p.Ser36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,551,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

CRYM
NM_001376256.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.879

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.071457565).

BP6

Variant 16-21278144-G-T is Benign according to our data. Variant chr16-21278144-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178331.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYM	NM_001376256.1 link	c.108C>A	p.Ser36Arg	missense_variant	Exon 1 of 8	ENST00000572914.2	NP_001363185.1
CRYM	NM_001888.5 link	c.108C>A	p.Ser36Arg	missense_variant	Exon 3 of 10		NP_001879.1	Q14894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYM	ENST00000572914.2 link	c.108C>A	p.Ser36Arg	missense_variant	Exon 1 of 8	2	NM_001376256.1	ENSP00000461904.2		Q14894I3NI53

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000314

AC:

AN:

155968

Hom.:

AF XY:

0.000388

AC XY:

AN XY:

82424

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.000469

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000873

Gnomad FIN exome

AF:

0.0000695

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.000512

AC:

716

AN:

1398910

Hom.:

Cov.:

AF XY:

0.000522

AC XY:

360

AN XY:

690224

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000363

Gnomad4 ASJ exome

AF:

0.000596

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000113

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000593

Gnomad4 OTH exome

AF:

0.000466

GnomAD4 genome

AF:

0.000296

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000460

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.000137

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Dec 05, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 26, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ser36Arg variant in CRYM has not been reported in individuals with hearing l oss, but has been identified in 0.03% (4/8420) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs147233841). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analy ses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ser36Arg variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The variant is c onserved in chimp, dog, cat, cow and frog but not in mouse and chicken. In summa ry, additional data is needed to determine the clinical significance of this var iant. -

not provided

Uncertain:1Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CRYM: BS2 -

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 36 of the CRYM protein (p.Ser36Arg). This variant is present in population databases (rs147233841, gnomAD 0.05%). This missense change has been observed in individual(s) with deafness (PMID: 36056583). ClinVar contains an entry for this variant (Variation ID: 178331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CRYM protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.48

M_CAP

Benign

0.017

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.035

N;N;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.21

N;N;.

REVEL

Benign

0.27

Sift

Benign

0.51

T;T;.

Sift4G

Benign

0.56

T;T;.

Polyphen

0.0040

B;B;.

Vest4

0.16

MutPred

0.55

Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);

MVP

0.71

MPC

0.37

ClinPred

0.022

GERP RS

2.7

Varity_R

0.21

gMVP

0.71

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