12-52768919-C-A

Variant names:

• chr12-52768919-C-A
• rs774475491
• NM_015848.4:c.1711G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015848.4(KRT76):​c.1711G>T​(p.Gly571Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G571S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRT76 NM_015848.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086396396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT76	NM_015848.4	c.1711G>T	p.Gly571Cys	missense_variant	Exon 9 of 9	ENST00000332411.2	NP_056932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT76	ENST00000332411.2	c.1711G>T	p.Gly571Cys	missense_variant	Exon 9 of 9	1	NM_015848.4	ENSP00000330101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443284 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 718242

African (AFR) AF: 0.0000302 AC: 1 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.00 AC: 0 AN: 85422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097730

Other (OTH) AF: 0.00 AC: 0 AN: 59638

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.0
DANN	Benign	0.90
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.30
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Benign	0.098	T
Sift4G	Benign	0.064	T
Polyphen		0.014	B
Vest4		0.16
MutPred		0.42		Gain of catalytic residue at S575 (P = 0.0019);
MVP		0.38
MPC		0.053
ClinPred		0.090	T
GERP RS		-0.030
Varity_R		0.16
gMVP		0.65
Mutation Taster		=93/7	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: rs774475491; hg19: chr12-53162703;