chr16-21258785-T-G

Variant names:

• chr16-21258785-T-G
• rs104894512
• NM_001376256.1:c.941A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001376256.1(CRYM):​c.941A>C​(p.Lys314Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 2.99
• Publications: 12 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 40

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	NM_001376256.1	MANE Select	c.941A>C	p.Lys314Thr	missense	Exon 8 of 8	NP_001363185.1
	CRYM	NM_001888.5		c.941A>C	p.Lys314Thr	missense	Exon 10 of 10	NP_001879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	ENST00000572914.2	TSL:2 MANE Select	c.941A>C	p.Lys314Thr	missense	Exon 8 of 8	ENSP00000461904.2
	CRYM	ENST00000219599.8	TSL:1	c.941A>C	p.Lys314Thr	missense	Exon 10 of 10	ENSP00000219599.3
	CRYM	ENST00000574448.5	TSL:1	n.*520+2469A>C		intron	N/A	ENSP00000459982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461380 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727048

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111602

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 40 Pathogenic:1

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.016	D
Polyphen		0.91	P
Vest4		0.25
MutPred		0.82		Loss of ubiquitination at K314 (P = 0.0192)
MVP		0.82
MPC		0.73
ClinPred		0.73	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.53
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs104894512; hg19: chr16-21270106;