Genetic Variant CRYM:p.Lys314Thr (chr16-21258785-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001376256.1(CRYM):c.941A>C(p.Lys314Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CRYM
NM_001376256.1 missense

Scores

Clinical Significance

no classifications from unflagged records no classifications from unflagged records P:1

Conservation

PhyloP100: 2.99

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 40
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CRYM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYM	NM_001376256.1 link	c.941A>C	p.Lys314Thr	missense_variant	Exon 8 of 8	ENST00000572914.2	NP_001363185.1
CRYM	NM_001888.5 link	c.941A>C	p.Lys314Thr	missense_variant	Exon 10 of 10		NP_001879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYM	ENST00000572914.2 link	c.941A>C	p.Lys314Thr	missense_variant	Exon 8 of 8	2	NM_001376256.1	ENSP00000461904.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461380

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111602

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 40

Pathogenic:1

Jan 01, 2003

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.0

.;.

M_CAP

Uncertain

0.085

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.0

N;N

PhyloP100

3.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.025

D;D

Sift4G

Uncertain

0.016

D;D

Vest4

0.25

ClinPred

0.73

GERP RS

5.5

Varity_R

0.11

gMVP

0.53

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over