17-40819093-C-G

Variant names:

• chr17-40819093-C-G
• rs554064245
• NM_000421.5:c.1442G>C

Variant summary

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

The NM_000421.5(KRT10):​c.1442G>C​(p.Gly481Ala) variant causes a missense 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. 16/22 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. G481E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.809
• Publications: 0 publications found

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.20176578).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000421.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	NM_000421.5	MANE Select	c.1442G>C	p.Gly481Ala	missense	Exon 7 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1442G>C	p.Gly481Ala	missense	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
	KRT10-AS1	NR_160886.1		n.-92C>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1442G>C	p.Gly481Ala	missense	Exon 7 of 8	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.1442G>C	p.Gly481Ala	missense	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
	KRT10-AS1	ENST00000436612.7	TSL:2	n.23C>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.81
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.95	P
Vest4		0.28
MutPred		0.26		Loss of loop (P = 0.0986)
MVP		0.76
MPC		0.45
ClinPred		0.32	T
GERP RS		3.6
Varity_R		0.27
gMVP		0.57

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: rs554064245; hg19: chr17-38975345;