rs386789728

Variant names:

• chr16-21267703-TC-AA
• rs386789728
• NM_001376256.1:c.523_524delGAinsTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001376256.1(CRYM):​c.523_524delGAinsTT​(p.Glu175Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000555 in 157 alleles, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E175V) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.00056 Genomes: not found (cov: 32)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.40
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 16-21267703-TC-AA is Benign according to our data. Variant chr16-21267703-TC-AA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179644.
• BS2: High AC in GnomAdMnv at 157 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.523_524delGAinsTT	p.Glu175Leu	missense	N/A	NP_001363185.1	Q14894
	CRYM	NM_001888.5		c.523_524delGAinsTT	p.Glu175Leu	missense	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.523_524delGAinsTT	p.Glu175Leu	missense	N/A	ENSP00000461904.2	Q14894
	CRYM	ENST00000219599.8	TSL:1	c.523_524delGAinsTT	p.Glu175Leu	missense	N/A	ENSP00000219599.3	Q14894
	CRYM	ENST00000574448.5	TSL:1	n.*163_*164delGAinsTT		non_coding_transcript_exon	Exon 6 of 10	ENSP00000459982.1	I3L2W5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.000555 AC: 157 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386789728; hg19: chr16-21279024;