NM_001376256.1:c.807T>C

Variant names:

• chr16-21261327-A-G
• rs144588424
• NM_001376256.1:c.807T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001376256.1(CRYM):​c.807T>C​(p.Phe269Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,054 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0054 (30 hom.)
• Consequence: CRYM NM_001376256.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.176
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-21261327-A-G is Benign according to our data. Variant chr16-21261327-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.176 with no splicing effect.
• BS2: High AC in GnomAd4 at 587 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.807T>C	p.Phe269Phe	synonymous	Exon 7 of 8	NP_001363185.1	Q14894
	CRYM	NM_001888.5		c.807T>C	p.Phe269Phe	synonymous	Exon 9 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.807T>C	p.Phe269Phe	synonymous	Exon 7 of 8	ENSP00000461904.2	Q14894
	CRYM	ENST00000219599.8	TSL:1	c.807T>C	p.Phe269Phe	synonymous	Exon 9 of 10	ENSP00000219599.3	Q14894
	CRYM	ENST00000574448.5	TSL:1	n.*447T>C		non_coding_transcript_exon	Exon 8 of 10	ENSP00000459982.1	I3L2W5

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 152124 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00385 AC: 969 AN: 251414 AF XY: 0.00379

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00832

Gnomad NFE exome AF: 0.00532

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00537 AC: 7849 AN: 1461812 Hom.: 30 Cov.: 33 AF XY: 0.00514 AC XY: 3740 AN XY: 727206

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86256

European-Finnish (FIN) AF: 0.00927 AC: 495 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00611 AC: 6797 AN: 1111944

Other (OTH) AF: 0.00401 AC: 242 AN: 60394

GnomAD4 genome AF: 0.00386 AC: 587 AN: 152242 Hom.: 3 Cov.: 30 AF XY: 0.00403 AC XY: 300 AN XY: 74438

African (AFR) AF: 0.000650 AC: 27 AN: 41546

American (AMR) AF: 0.00458 AC: 70 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

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

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4802

European-Finnish (FIN) AF: 0.00867 AC: 92 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00560 AC: 381 AN: 68028

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00335

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.1
DANN	Benign	0.68
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism

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: rs144588424; hg19: chr16-21272648;