rs34045013

Variant names:

• chr16-21262091-G-A
• rs34045013
• NM_001376256.1:c.741C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-21262091-G-A
• chr16-21262091-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001376256.1(CRYM):​c.741C>T​(p.Tyr247Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,110 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: CRYM NM_001376256.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.385
• Publications: 6 publications found

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]

CRYM Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 40

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-21262091-G-A is Benign according to our data. Variant chr16-21262091-G-A is described in ClinVar as Benign. ClinVar VariationId is 163002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.385 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1626/152266) while in subpopulation AFR AF = 0.0372 (1547/41540). AF 95% confidence interval is 0.0357. There are 28 homozygotes in GnomAd4. There are 741 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1626 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376256.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	NM_001376256.1	MANE Select	c.741C>T	p.Tyr247Tyr	synonymous	Exon 6 of 8	NP_001363185.1	Q14894
	CRYM	NM_001888.5		c.741C>T	p.Tyr247Tyr	synonymous	Exon 8 of 10	NP_001879.1	Q14894

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	ENST00000572914.2	TSL:2 MANE Select	c.741C>T	p.Tyr247Tyr	synonymous	Exon 6 of 8	ENSP00000461904.2	Q14894
	CRYM	ENST00000219599.8	TSL:1	c.741C>T	p.Tyr247Tyr	synonymous	Exon 8 of 10	ENSP00000219599.3	Q14894
	CRYM	ENST00000574448.5	TSL:1	n.*381C>T		non_coding_transcript_exon	Exon 7 of 10	ENSP00000459982.1	I3L2W5

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1627 AN: 152148 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00287 AC: 719 AN: 250804 AF XY: 0.00209

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00110 AC: 1603 AN: 1461844 Hom.: 27 Cov.: 31 AF XY: 0.000928 AC XY: 675 AN XY: 727220

African (AFR) AF: 0.0385 AC: 1288 AN: 33478

American (AMR) AF: 0.00206 AC: 92 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111990

Other (OTH) AF: 0.00224 AC: 135 AN: 60394

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152266 Hom.: 28 Cov.: 32 AF XY: 0.00995 AC XY: 741 AN XY: 74456

African (AFR) AF: 0.0372 AC: 1547 AN: 41540

American (AMR) AF: 0.00392 AC: 60 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00841 Hom.: 18

Bravo AF: 0.0121

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 40 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.33
DANN	Benign	0.44
PhyloP100		-0.39
PromoterAI		-0.047	Neutral
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs34045013; hg19: chr16-21273412;