chr16-21258783-A-G

Variant names:

• chr16-21258783-A-G
• rs140779001
• NM_001376256.1:c.943T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_001376256.1(CRYM):​c.943T>C​(p.Ter315Glnext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000335 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CRYM NM_001376256.1 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM4: Stoplost variant in NM_001376256.1 Downstream stopcodon found after 327 codons.
• BS2: High AC in GnomAd4 at 30 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.943T>C	p.Ter315Glnext*?	stop_lost	Exon 8 of 8	NP_001363185.1	Q14894
	CRYM	NM_001888.5		c.943T>C	p.Ter315Glnext*?	stop_lost	Exon 10 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.943T>C	p.Ter315Glnext*?	stop_lost	Exon 8 of 8	ENSP00000461904.2	Q14894
	CRYM	ENST00000219599.8	TSL:1	c.943T>C	p.Ter315Glnext*?	stop_lost	Exon 10 of 10	ENSP00000219599.3	Q14894
	CRYM	ENST00000574448.5	TSL:1	n.*520+2471T>C		intron	N/A	ENSP00000459982.1	I3L2W5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000796 AC: 20 AN: 251206 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461296 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727018

African (AFR) AF: 0.000627 AC: 21 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111532

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74472

African (AFR) AF: 0.000721 AC: 30 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nonsyndromic hearing loss 40 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.81
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.0
Vest4		0.14
GERP RS		5.5

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: rs140779001; hg19: chr16-21270104;