12-52769570-A-G

Position:

• chr12-52769570-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015848.4(KRT76):​c.1498T>C​(p.Cys500Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: KRT76 NM_015848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

Genes affected

KRT76 (HGNC:24430): (keratin 76) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. The type II keratins are clustered in a region of chromosome 12q13. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22143105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT76	NM_015848.4	c.1498T>C	p.Cys500Arg	missense_variant	8/9	ENST00000332411.2	NP_056932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT76	ENST00000332411.2	c.1498T>C	p.Cys500Arg	missense_variant	8/9	1	NM_015848.4	ENSP00000330101.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461576 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727124

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: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.1498T>C (p.C500R) alteration is located in exon 8 (coding exon 8) of the KRT76 gene. This alteration results from a T to C substitution at nucleotide position 1498, causing the cysteine (C) at amino acid position 500 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.00098	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.30
Sift	Benign	0.27	T
Sift4G	Benign	0.32	T
Polyphen		0.12	B
Vest4		0.56
MutPred		0.50		Gain of solvent accessibility (P = 0.0171);
MVP		0.65
MPC		0.36
ClinPred		0.71	D
GERP RS		3.7
Varity_R		0.41
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs756652327; hg19: chr12-53163354;