rs226039

Variant names:

• chr16-21276780-A-G
• rs226039
• NM_001376256.1:c.324+651T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376256.1(CRYM):​c.324+651T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,070 control chromosomes in the GnomAD database, including 5,932 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5932 hom., cov: 32)
• Consequence: CRYM NM_001376256.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.284
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

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.324+651T>C		intron	N/A	NP_001363185.1
	CRYM	NM_001888.5		c.324+651T>C		intron	N/A	NP_001879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	ENST00000572914.2	TSL:2 MANE Select	c.324+651T>C		intron	N/A	ENSP00000461904.2
	CRYM	ENST00000219599.8	TSL:1	c.324+651T>C		intron	N/A	ENSP00000219599.3
	CRYM	ENST00000574448.5	TSL:1	n.324+651T>C		intron	N/A	ENSP00000459982.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40813 AN: 151952 Hom.: 5926 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.209

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.269 AC: 40845 AN: 152070 Hom.: 5932 Cov.: 32 AF XY: 0.266 AC XY: 19801 AN XY: 74350

African (AFR) AF: 0.362 AC: 15008 AN: 41460

American (AMR) AF: 0.212 AC: 3242 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 647 AN: 3466

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.170 AC: 821 AN: 4826

European-Finnish (FIN) AF: 0.293 AC: 3095 AN: 10560

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17205 AN: 67962

Other (OTH) AF: 0.206 AC: 435 AN: 2112

Alfa AF: 0.253 Hom.: 14107

Bravo AF: 0.264

Asia WGS AF: 0.0970 AC: 340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.1
DANN	Benign	0.67
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs226039; hg19: chr16-21288101;