12-52691972-C-T

Position:

• chr12-52691972-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The ENST00000341809.8(KRT77):​c.1428G>A​(p.Arg476=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT77 ENST00000341809.8 splice_region, synonymous
• Scores: Splicing: ADA: 0.8532
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.815

Genes affected

KRT77 (HGNC:20411): (keratin 77) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene encodes an epithelial keratin that is expressed in the skin and eccrine sweat glands. The type II keratins are clustered in a region of chromosome 12q13.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 12-52691972-C-T is Benign according to our data. Variant chr12-52691972-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3289537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.815 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT77	NM_175078.3	c.1428G>A	p.Arg476=	splice_region_variant, synonymous_variant	8/9	ENST00000341809.8	NP_778253.2
KRT77	XM_011538288.3	c.729G>A	p.Arg243=	splice_region_variant, synonymous_variant	8/9		XP_011536590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT77	ENST00000341809.8	c.1428G>A	p.Arg476=	splice_region_variant, synonymous_variant	8/9	1	NM_175078.3	ENSP00000342710	P1
KRT77	ENST00000553168.1	c.*766G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	9/10	1		ENSP00000448207

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs778191928; hg19: chr12-53085756;