chr17-40818434-G-T

Variant names:

• chr17-40818434-G-T
• rs71371449
• NM_000421.5:c.*42C>A

Variant summary

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

The NM_001379366.1(KRT10):​c.1817C>A​(p.Pro606His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/9 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. P606L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT10 NM_001379366.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48
• 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 Gene-Disease associations (from GenCC):

• annular epidermolytic ichthyosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, G2P
• congenital reticular ichthyosiform erythroderma

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet
• epidermolytic hyperkeratosis 2A, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• epidermolytic ichthyosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• ichthyosis, annular epidermolytic 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epidermolytic hyperkeratosis 2B, autosomal recessive

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• autosomal recessive epidermolytic ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=0.26133233).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379366.1. 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.*42C>A		3_prime_UTR	Exon 8 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1817C>A	p.Pro606His	missense	Exon 8 of 8	NP_001366295.1	A0A1B0GVI3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.*42C>A		3_prime_UTR	Exon 8 of 8	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.1817C>A	p.Pro606His	missense	Exon 8 of 8	ENSP00000490524.2	A0A1B0GVI3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461130 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111514

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.081	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.26	T
PhyloP100		3.5
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs71371449; hg19: chr17-38974686;