16-21258841-C-A

Variant names:

• chr16-21258841-C-A
• rs533525035
• NM_001376256.1:c.885G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001376256.1(CRYM):​c.885G>T​(p.Met295Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.28
• Publications: 0 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: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 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.885G>T	p.Met295Ile	missense	Exon 8 of 8	NP_001363185.1	Q14894
	CRYM	NM_001888.5		c.885G>T	p.Met295Ile	missense	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.885G>T	p.Met295Ile	missense	Exon 8 of 8	ENSP00000461904.2	Q14894
	CRYM	ENST00000219599.8	TSL:1	c.885G>T	p.Met295Ile	missense	Exon 10 of 10	ENSP00000219599.3	Q14894
	CRYM	ENST00000574448.5	TSL:1	n.*520+2413G>T		intron	N/A	ENSP00000459982.1	I3L2W5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251238 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461760 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

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

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Benign	0.19	T
Sift4G	Benign	0.17	T
Polyphen		0.37	B
Vest4		0.44
MutPred		0.53		Loss of phosphorylation at T300 (P = 0.0762)
MVP		0.80
MPC		0.55
ClinPred		0.82	D
GERP RS		4.5
Varity_R		0.70
gMVP		0.68
Mutation Taster		=31/69	disease causing

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: rs533525035; hg19: chr16-21270162;