rs149797560

Positions:

• chr16-21278244-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001376256.1(CRYM):​c.8G>T​(p.Arg3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,584,580 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.107

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043696165).
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1	c.8G>T	p.Arg3Leu	missense_variant	1/8	ENST00000572914.2
CRYM	NM_001888.5	c.8G>T	p.Arg3Leu	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2	c.8G>T	p.Arg3Leu	missense_variant	1/8	2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 38 AN: 206782 Hom.: 0 AF XY: 0.000170 AC XY: 19 AN XY: 111970

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00116

Gnomad SAS exome AF: 0.000573

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.000103 AC: 148 AN: 1432272 Hom.: 1 Cov.: 32 AF XY: 0.000128 AC XY: 91 AN XY: 710568

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000662

Gnomad4 SAS exome AF: 0.000876

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.000707

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74470

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000416 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 21, 2023	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3 of the CRYM protein (p.Arg3Leu). ClinVar contains an entry for this variant (Variation ID: 289303). This variant has not been reported in the literature in individuals affected with CRYM-related conditions. This variant is present in population databases (rs149797560, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T;T;T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;N;.;.
REVEL	Benign	0.17
Sift	Benign	0.26	T;T;.;.
Sift4G	Benign	0.29	T;T;.;.
Polyphen		0.0	B;B;.;.
Vest4		0.091
MVP		0.57
MPC		0.40
ClinPred		0.026	T
GERP RS		1.5
Varity_R		0.32
gMVP		0.74

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: rs149797560; hg19: chr16-21289565;