16-21258783-A-G

Variant names:

• chr16-21258783-A-G
• rs140779001
• NM_001376256.1:c.943T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_001376256.1(CRYM):​c.943T>C​(p.Ter315Glnext*?) 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_001376256.1 Downstream stopcodon found after 327 codons.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYM	NM_001376256.1	c.943T>C	p.Ter315Glnext*?	stop_lost	Exon 8 of 8	ENST00000572914.2	NP_001363185.1
CRYM	NM_001888.5	c.943T>C	p.Ter315Glnext*?	stop_lost	Exon 10 of 10		NP_001879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYM	ENST00000572914.2	c.943T>C	p.Ter315Glnext*?	stop_lost	Exon 8 of 8	2	NM_001376256.1	ENSP00000461904.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152212 Hom.: 0 Cov.: 32

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: 20 AN: 251206 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135762

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: 24 AN: 1461296 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727018

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: 30 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74472

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.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 40 Uncertain:1

Sep 26, 2019

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.81
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
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

Other links and lift over

dbSNP: rs140779001; hg19: chr16-21270104;