rs226052

Positions:

• chr16-21267749-G-A

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.490-12C>T 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 0.0169 in 1,613,984 control chromosomes in the GnomAD database, including 3,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1918 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (1703 hom.)
• Consequence: CRYM NM_001376256.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003459
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.36

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=-0.71).
• BP6: Variant 16-21267749-G-A is Benign according to our data. Variant chr16-21267749-G-A is described in ClinVar as [Benign]. Clinvar id is 44240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21267749-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1	c.490-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000572914.2
CRYM	NM_001888.5	c.490-12C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2	c.490-12C>T		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13191 AN: 152120 Hom.: 1909 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.0621

GnomAD3 exomes AF: 0.0231 AC: 5808 AN: 251278 Hom.: 777 AF XY: 0.0173 AC XY: 2348 AN XY: 135806

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00959 AC: 14020 AN: 1461746 Hom.: 1703 Cov.: 31 AF XY: 0.00831 AC XY: 6044 AN XY: 727178

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000854

Gnomad4 OTH exome AF: 0.0216

GnomAD4 genome AF: 0.0870 AC: 13238 AN: 152238 Hom.: 1918 Cov.: 32 AF XY: 0.0840 AC XY: 6250 AN XY: 74434

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.0614

Alfa AF: 0.0452 Hom.: 244

Bravo AF: 0.0999

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	490-12C>T in Intron 06 of CRYM: This variant is not expected to have clinical si gnificance because it has been identified in 27.9% (1043/3738) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs226052). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.4
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.074
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: rs226052; hg19: chr16-21279070;