rs104894512

chr16-21258785-T-Cchr16-21258785-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001376256.1(CRYM):c.941A>G(p.Lys314Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. K314T) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-21258785-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 16935.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3451909).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1	c.941A>G	p.Lys314Arg	missense_variant	8/8	ENST00000572914.2
CRYM	NM_001888.5	c.941A>G	p.Lys314Arg	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2	c.941A>G	p.Lys314Arg	missense_variant	8/8	2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	0.071
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	0.67	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.23	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.22	T;T
Sift4G	Benign	0.075	T;T
Polyphen		0.91	P;P
Vest4		0.31
MutPred		0.49		Loss of ubiquitination at K314 (P = 0.0192);Loss of ubiquitination at K314 (P = 0.0192);
MVP		0.82
MPC		0.28
ClinPred		0.79	D
GERP RS		5.5
Varity_R		0.072
gMVP		0.33

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: rs104894512; hg19: chr16-21270106;