chr16-21275606-A-G

Variant names:

• chr16-21275606-A-G
• rs226045
• NM_001376256.1:c.325-12T>C

Variant summary

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

The ENST00000572914.2(CRYM):​c.325-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,609,228 control chromosomes in the GnomAD database, including 52,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5930 hom., cov: 32)
  • Exomes 𝑓: 0.24 (46264 hom.)
• Consequence: CRYM ENST00000572914.2 intron
• Scores: Splicing: ADA: 0.0001049
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00100
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-21275606-A-G is Benign according to our data. Variant chr16-21275606-A-G is described in ClinVar as Benign. ClinVar VariationId is 44237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000572914.2. 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.325-12T>C		intron	N/A	NP_001363185.1
	CRYM	NM_001888.5		c.325-12T>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.325-12T>C		intron	N/A	ENSP00000461904.2
	CRYM	ENST00000219599.8	TSL:1	c.325-12T>C		intron	N/A	ENSP00000219599.3
	CRYM	ENST00000574448.5	TSL:1	n.325-12T>C		intron	N/A	ENSP00000459982.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40801 AN: 151968 Hom.: 5924 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: 0.292

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.225 AC: 56578 AN: 250966 AF XY: 0.226

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.244 AC: 355862 AN: 1457142 Hom.: 46264 Cov.: 30 AF XY: 0.243 AC XY: 176043 AN XY: 725170

African (AFR) AF: 0.359 AC: 12000 AN: 33386

American (AMR) AF: 0.178 AC: 7962 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4907 AN: 26096

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39692

South Asian (SAS) AF: 0.196 AC: 16849 AN: 86170

European-Finnish (FIN) AF: 0.293 AC: 15656 AN: 53352

Middle Eastern (MID) AF: 0.233 AC: 1341 AN: 5760

European-Non Finnish (NFE) AF: 0.256 AC: 283170 AN: 1107736

Other (OTH) AF: 0.231 AC: 13932 AN: 60240

GnomAD4 genome AF: 0.268 AC: 40833 AN: 152086 Hom.: 5930 Cov.: 32 AF XY: 0.266 AC XY: 19786 AN XY: 74350

African (AFR) AF: 0.362 AC: 15002 AN: 41466

American (AMR) AF: 0.212 AC: 3235 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 647 AN: 3468

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

South Asian (SAS) AF: 0.170 AC: 822 AN: 4824

European-Finnish (FIN) AF: 0.292 AC: 3089 AN: 10574

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.253 AC: 17208 AN: 67966

Other (OTH) AF: 0.207 AC: 439 AN: 2116

Alfa AF: 0.255 Hom.: 1704

Bravo AF: 0.264

Asia WGS AF: 0.0970 AC: 340 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 40 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		-0.0010
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.028
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs226045; hg19: chr16-21286927; COSMIC: COSV54831703; COSMIC: COSV54831703;