12-52897550-C-T

Variant summary

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

The NM_002273.4(KRT8):c.1330G>A(p.Gly444Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,445,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000021 (0 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.992

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12628767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT8	NM_002273.4	c.1330G>A	p.Gly444Ser	missense_variant	8/8	ENST00000692008.1
KRT8	NM_001256282.2	c.1414G>A	p.Gly472Ser	missense_variant	9/9
KRT8	NM_001256293.2	c.1330G>A	p.Gly444Ser	missense_variant	9/9
KRT8	NR_045962.2	n.1781G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT8	ENST00000692008.1	c.1330G>A	p.Gly444Ser	missense_variant	8/8		NM_002273.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445006 Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 2 AN XY: 719316

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 33

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 24, 2024

The c.1330G>A (p.G444S) alteration is located in exon 8 (coding exon 8) of the KRT8 gene. This alteration results from a G to A substitution at nucleotide position 1330, causing the glycine (G) at amino acid position 444 to be replaced by a serine (S). 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	Benign	0.078
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	2.8
Dann	Benign	0.95
DEOGEN2	Benign	0.34	T;T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.19	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.26
MutPred		0.14		Gain of phosphorylation at G444 (P = 0.0075);Gain of phosphorylation at G444 (P = 0.0075);Gain of phosphorylation at G444 (P = 0.0075);.;
MVP		0.74
MPC		1.4
ClinPred		0.60	D
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53291334;