chr13-94443496-TAGTCACTGGAGGGA-T

Position:

• chr13-94443496-TAGTCACTGGAGGGA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001922.5(DCT):​c.1307_1320del​(p.Phe436Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DCT NM_001922.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 10.0

Genes affected

DCT (HGNC:2709): (dopachrome tautomerase) Predicted to enable dopachrome isomerase activity. Involved in response to blue light. Located in intracellular membrane-bounded organelle and plasma membrane. Implicated in oculocutaneous albinism. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.162 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-94443496-TAGTCACTGGAGGGA-T is Pathogenic according to our data. Variant chr13-94443496-TAGTCACTGGAGGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 930182.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCT	NM_001922.5	c.1307_1320del	p.Phe436Ter	frameshift_variant	7/8	ENST00000377028.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCT	ENST00000377028.10	c.1307_1320del	p.Phe436Ter	frameshift_variant	7/8	1	NM_001922.5	P1
DCT	ENST00000446125.1	c.1406_1419del	p.Phe469Ter	frameshift_variant	9/10	1
DCT	ENST00000483392.6	c.*182_*195del		3_prime_UTR_variant, NMD_transcript_variant	8/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461792 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Oculocutaneous albinism type 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 20, 2021

- -

Albinism Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratoire de Genetique Moleculaire, Centre Hospitalier Universitaire de Bordeaux

Jun 15, 2020

We sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients in order to search for new mutations. In two unrelated patients we identified variants in the Dopachrome tautomerase (DCT) (also called Tyrosinase-related protein 2, TYRP2) gene. One patient was compound heterozygous for a 14 bp deletion in exon 9 and a c.118T>A p.(Cys40Ser) variant. The second patient was homozygous for a c.183C>G p.(Cys61Trp) variant. Both patients had mild hair and skin hypopigmentation, and classical ocular features including nystagmus, iris and retinal hypopigmentation. We have used CRISPR/Cas9 in C57BL/6J mice to create mutations identical to the missense mutations carried by these two patients, along with one loss-of-function indel mutation. When bred to homozygosity these novel mouse mutations revealed different degrees of hypopigmentation of the coat, milder for Cys40Ser compared to Cys61Trp or the frameshift mutation. Histological analysis of the retina identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that a defect in RPE melanogenesis could be associated with eye and vision defects in DCT patients. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1882493359; hg19: chr13-95095750;