Genetic Variant CRYM:p.Arg3Gln (chr16-21278244-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001376256.1(CRYM):c.8G>A(p.Arg3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CRYM
NM_001376256.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.107

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055748135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376256.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	NM_001376256.1	MANE Select	c.8G>A	p.Arg3Gln	missense	Exon 1 of 8	NP_001363185.1
	CRYM	NM_001888.5		c.8G>A	p.Arg3Gln	missense	Exon 3 of 10	NP_001879.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRYM	ENST00000572914.2	TSL:2 MANE Select	c.8G>A	p.Arg3Gln	missense	Exon 1 of 8	ENSP00000461904.2
CRYM	ENST00000219599.8	TSL:1	c.8G>A	p.Arg3Gln	missense	Exon 3 of 10	ENSP00000219599.3
CRYM	ENST00000574448.5	TSL:1	n.8G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000459982.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1432272

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32622

American (AMR)

AF:

0.00

AC:

AN:

41908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25708

East Asian (EAS)

AF:

0.00

AC:

AN:

37786

South Asian (SAS)

AF:

0.00

AC:

AN:

82238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1101166

Other (OTH)

AF:

0.00

AC:

AN:

59420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.0083

M_CAP

Benign

0.045

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

PhyloP100

-0.11

PrimateAI

Benign

0.40

PROVEAN

Benign

0.19

REVEL

Benign

0.16

Sift

Benign

0.50

Sift4G

Benign

0.58

Polyphen

0.013

Vest4

0.10

MutPred

0.48

Gain of sheet (P = 0.0266)

MVP

0.47

MPC

0.37

ClinPred

0.088

GERP RS

1.5

PromoterAI

-0.094

Neutral

(source)

Varity_R

0.18

gMVP

0.66

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over