NM_173853.4:c.37C>T

Variant names:

• chr2-27442587-C-T
• rs1253462644
• NM_173853.4:c.37C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173853.4(KRTCAP3):​c.37C>T​(p.Arg13Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRTCAP3 NM_173853.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.697
• Publications: 0 publications found

Genes affected

KRTCAP3 (HGNC:28943): (keratinocyte associated protein 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3293504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173853.4. 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
	KRTCAP3	NM_173853.4	MANE Select	c.37C>T	p.Arg13Trp	missense	Exon 2 of 7	NP_776252.2	Q53RY4-1
	KRTCAP3	NM_001168364.2		c.37C>T	p.Arg13Trp	missense	Exon 2 of 7	NP_001161836.1	Q53RY4-1
	KRTCAP3	NM_001321325.2		c.37C>T	p.Arg13Trp	missense	Exon 2 of 7	NP_001308254.1	Q53RY4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTCAP3	ENST00000288873.7	TSL:1 MANE Select	c.37C>T	p.Arg13Trp	missense	Exon 2 of 7	ENSP00000288873.3	Q53RY4-1
	KRTCAP3	ENST00000407293.5	TSL:2	c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000384689.1	Q53RY4-2
	KRTCAP3	ENST00000543753.5	TSL:5	c.37C>T	p.Arg13Trp	missense	Exon 2 of 7	ENSP00000442400.1	Q53RY4-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000668 AC: 1 AN: 149618 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000274

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380376 Hom.: 0 Cov.: 33 AF XY: 0.00000294 AC XY: 2 AN XY: 679724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31024

American (AMR) AF: 0.00 AC: 0 AN: 30568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21430

East Asian (EAS) AF: 0.00 AC: 0 AN: 37944

South Asian (SAS) AF: 0.00 AC: 0 AN: 74040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48946

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5442

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074124

Other (OTH) AF: 0.0000176 AC: 1 AN: 56858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.70
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.97	D
Vest4		0.39
MutPred		0.42		Loss of solvent accessibility (P = 0.0087)
MVP		0.39
MPC		0.30
ClinPred		0.75	D
GERP RS		4.1
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.50
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1253462644; hg19: chr2-27665454;