rs144588424

Positions:

• chr16-21261327-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001376256.1(CRYM):​c.807T>C​(p.Phe269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,054 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0054 (30 hom.)
• Consequence: CRYM NM_001376256.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.176

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-21261327-A-G is Benign according to our data. Variant chr16-21261327-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 178330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21261327-A-G is described in Lovd as [Likely_benign]. Variant chr16-21261327-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.176 with no splicing effect.
• BS2: High AC in GnomAd4 at 587 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYM	NM_001376256.1	c.807T>C	p.Phe269=	synonymous_variant	7/8	ENST00000572914.2	NP_001363185.1
CRYM	NM_001888.5	c.807T>C	p.Phe269=	synonymous_variant	9/10		NP_001879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYM	ENST00000572914.2	c.807T>C	p.Phe269=	synonymous_variant	7/8	2	NM_001376256.1	ENSP00000461904	P1

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 152124 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00385 AC: 969 AN: 251414 Hom.: 6 AF XY: 0.00379 AC XY: 515 AN XY: 135884

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00832

Gnomad NFE exome AF: 0.00532

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00537 AC: 7849 AN: 1461812 Hom.: 30 Cov.: 33 AF XY: 0.00514 AC XY: 3740 AN XY: 727206

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.00927

Gnomad4 NFE exome AF: 0.00611

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.00386 AC: 587 AN: 152242 Hom.: 3 Cov.: 30 AF XY: 0.00403 AC XY: 300 AN XY: 74438

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.00560

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00335

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CRYM: BP4, BP7, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Phe269Phe in Exon 09 of CRYM: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.6% (42/7020) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144588424). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.1
DANN	Benign	0.68

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: rs144588424; hg19: chr16-21272648;