rs226045

Positions:

• chr16-21275606-A-G
• chr16-21275606-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376256.1(CRYM):​c.325-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,609,228 control chromosomes in the GnomAD database, including 52,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5930 hom., cov: 32)
  • Exomes 𝑓: 0.24 (46264 hom.)
• Consequence: CRYM NM_001376256.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001049
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-21275606-A-G is Benign according to our data. Variant chr16-21275606-A-G is described in ClinVar as [Benign]. Clinvar id is 44237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21275606-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1	c.325-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000572914.2
CRYM	NM_001888.5	c.325-12T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2	c.325-12T>C		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40801 AN: 151968 Hom.: 5924 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.225 AC: 56578 AN: 250966 Hom.: 7400 AF XY: 0.226 AC XY: 30606 AN XY: 135638

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.244 AC: 355862 AN: 1457142 Hom.: 46264 Cov.: 30 AF XY: 0.243 AC XY: 176043 AN XY: 725170

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.268 AC: 40833 AN: 152086 Hom.: 5930 Cov.: 32 AF XY: 0.266 AC XY: 19786 AN XY: 74350

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.207

Alfa AF: 0.251 Hom.: 914

Bravo AF: 0.264

Asia WGS AF: 0.0970 AC: 340 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	325-12T>C in Intron 04 of CRYM: This variant is not expected to have clinical si gnificance because it has been identified in 36.1% (1351/3738) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs226045). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -

Autosomal dominant nonsyndromic hearing loss 40 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.020		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: rs226045; hg19: chr16-21286927; COSMIC: COSV54831703; COSMIC: COSV54831703;