2-27442651-T-C

Variant names:

• chr2-27442651-T-C
• rs1664679383
• NM_173853.4:c.101T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173853.4(KRTCAP3):​c.101T>C​(p.Leu34Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000038 in 1,579,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L34Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KRTCAP3 NM_173853.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.85
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

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.101T>C	p.Leu34Pro	missense	Exon 2 of 7	NP_776252.2	Q53RY4-1
	KRTCAP3	NM_001168364.2		c.101T>C	p.Leu34Pro	missense	Exon 2 of 7	NP_001161836.1	Q53RY4-1
	KRTCAP3	NM_001321325.2		c.101T>C	p.Leu34Pro	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.101T>C	p.Leu34Pro	missense	Exon 2 of 7	ENSP00000288873.3	Q53RY4-1
	KRTCAP3	ENST00000543753.5	TSL:5	c.101T>C	p.Leu34Pro	missense	Exon 2 of 7	ENSP00000442400.1	Q53RY4-1
	KRTCAP3	ENST00000872248.1		c.101T>C	p.Leu34Pro	missense	Exon 2 of 7	ENSP00000542307.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1427456 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 707078

African (AFR) AF: 0.0000308 AC: 1 AN: 32464

American (AMR) AF: 0.00 AC: 0 AN: 40010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 81320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1095286

Other (OTH) AF: 0.0000170 AC: 1 AN: 58658

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.67		Loss of stability (P = 0.0133)
MVP		0.75
MPC		0.76
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.0046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.93
gMVP		0.83
Mutation Taster		=33/67	disease causing

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: rs1664679383; hg19: chr2-27665518;