16-21275576-T-G

Variant names:

• chr16-21275576-T-G
• NM_001376256.1:c.343A>C

Variant summary

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

The NM_001376256.1(CRYM):​c.343A>C​(p.Ile115Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I115V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.55

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 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	c.343A>C	p.Ile115Leu	missense_variant	Exon 3 of 8	ENST00000572914.2	NP_001363185.1
CRYM	NM_001888.5	c.343A>C	p.Ile115Leu	missense_variant	Exon 5 of 10		NP_001879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYM	ENST00000572914.2	c.343A>C	p.Ile115Leu	missense_variant	Exon 3 of 8	2	NM_001376256.1	ENSP00000461904.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727176

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D;D;.;T
Eigen	Benign	0.095
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L;L;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;N;.;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Benign	0.079	T;T;.;.
Polyphen		0.48	P;P;.;.
Vest4		0.71
MutPred		0.64		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);.;Loss of sheet (P = 0.0228);
MVP		0.71
MPC		0.71
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.88
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-21286897;