chr16-21267749-G-A

Variant names:

• chr16-21267749-G-A
• rs226052
• NM_001376256.1:c.490-12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376256.1(CRYM):​c.490-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,984 control chromosomes in the GnomAD database, including 3,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1918 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (1703 hom.)
• Consequence: CRYM NM_001376256.1 intron
• Scores: Splicing: ADA: 0.00003459
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.36
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-21267749-G-A is Benign according to our data. Variant chr16-21267749-G-A is described in ClinVar as Benign. ClinVar VariationId is 44240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYM	NM_001376256.1	MANE Select	c.490-12C>T		intron	N/A	NP_001363185.1	Q14894
	CRYM	NM_001888.5		c.490-12C>T		intron	N/A	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.490-12C>T		intron	N/A	ENSP00000461904.2	Q14894
	CRYM	ENST00000219599.8	TSL:1	c.490-12C>T		intron	N/A	ENSP00000219599.3	Q14894
	CRYM	ENST00000574448.5	TSL:1	n.*130-12C>T		intron	N/A	ENSP00000459982.1	I3L2W5

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13191 AN: 152120 Hom.: 1909 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0231 AC: 5808 AN: 251278 AF XY: 0.0173

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00959 AC: 14020 AN: 1461746 Hom.: 1703 Cov.: 31 AF XY: 0.00831 AC XY: 6044 AN XY: 727178

African (AFR) AF: 0.309 AC: 10356 AN: 33470

American (AMR) AF: 0.0193 AC: 863 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 353 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000939 AC: 81 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5766

European-Non Finnish (NFE) AF: 0.000854 AC: 950 AN: 1111894

Other (OTH) AF: 0.0216 AC: 1307 AN: 60394

GnomAD4 genome AF: 0.0870 AC: 13238 AN: 152238 Hom.: 1918 Cov.: 32 AF XY: 0.0840 AC XY: 6250 AN XY: 74434

African (AFR) AF: 0.297 AC: 12333 AN: 41488

American (AMR) AF: 0.0409 AC: 625 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

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

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68036

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0327 Hom.: 407

Bravo AF: 0.0999

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.4
DANN	Benign	0.71
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.074
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: rs226052; hg19: chr16-21279070;