rs876657447

chr16-21267565-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001376256.1(CRYM):c.662C>T(p.Ala221Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.12

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-21267565-G-A is Benign according to our data. Variant chr16-21267565-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227278.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1	c.662C>T	p.Ala221Val	missense_variant	5/8	ENST00000572914.2
CRYM	NM_001888.5	c.662C>T	p.Ala221Val	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2	c.662C>T	p.Ala221Val	missense_variant	5/8	2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461474 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 20, 2015

p.Ala221Val in exon 7 of CRYM: This variant is not expected to have clinical si gnificance because the alanine (Ala) residue at position 221 is not conserved th rough species, with alpaca and bactrian-camel having a valine (Val) at this posi tion. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Benign	0.014
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.41
Sift	Benign	0.24	T;T;.
Sift4G	Benign	0.42	T;T;.
Polyphen		0.82	P;P;.
Vest4		0.52
MutPred		0.57		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.81
MPC		0.37
ClinPred		0.78	D
GERP RS		3.8
Varity_R		0.58
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657447; hg19: chr16-21278886;