12-52897592-G-A

Variant names:

• chr12-52897592-G-A
• rs751726406
• NM_002273.4:c.1288C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002273.4(KRT8):​c.1288C>T​(p.Leu430Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,796 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52

Genes affected

KRT8 (HGNC:6446): (keratin 8) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38865882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT8	NM_002273.4	c.1288C>T	p.Leu430Phe	missense_variant	Exon 8 of 8	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2	c.1372C>T	p.Leu458Phe	missense_variant	Exon 9 of 9		NP_001243211.1
KRT8	NM_001256293.2	c.1288C>T	p.Leu430Phe	missense_variant	Exon 9 of 9		NP_001243222.1
KRT8	NR_045962.2	n.1739C>T		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1	c.1288C>T	p.Leu430Phe	missense_variant	Exon 8 of 8		NM_002273.4	ENSP00000509398.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445796 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719658

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;T;.
Eigen	Benign	-0.014
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.11	.;.;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L;L;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.070	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.013	B;B;B;.
Vest4		0.39
MutPred		0.14		Loss of glycosylation at S425 (P = 0.0709);Loss of glycosylation at S425 (P = 0.0709);Loss of glycosylation at S425 (P = 0.0709);.;
MVP		0.89
MPC		0.70
ClinPred		0.57	D
GERP RS		3.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.10
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs751726406; hg19: chr12-53291376;