Genetic Variant KRTAP2-4:p.Gly114Ser (chr17-41065506-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033184.4(KRTAP2-4):c.340G>A(p.Gly114Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,405,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. G114D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

KRTAP2-4
NM_033184.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.21

Publications

0 publications found

Variant links:

Genes affected

KRTAP2-4 (HGNC:18891): (keratin associated protein 2-4) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the high sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

KRTAP2-4 links:

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ACMG classification

Classification was made for transcript

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=0.09390378).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033184.4. 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
	KRTAP2-4	NM_033184.4	MANE Select	c.340G>A	p.Gly114Ser	missense	Exon 1 of 1	NP_149440.1	Q9BYR9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP2-4	ENST00000394015.3	TSL:6 MANE Select	c.340G>A	p.Gly114Ser	missense	Exon 1 of 1	ENSP00000377583.2	Q9BYR9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1405654

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694280

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32458

American (AMR)

AF:

0.00

AC:

AN:

36014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24820

East Asian (EAS)

AF:

0.00

AC:

AN:

37834

South Asian (SAS)

AF:

0.00

AC:

AN:

79532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084778

Other (OTH)

AF:

0.00

AC:

AN:

58390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.00076

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.0010

FATHMM_MKL

Benign

0.53

M_CAP

Benign

0.0030

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.99

PhyloP100

2.2

PrimateAI

Benign

0.39

PROVEAN

Benign

1.6

REVEL

Benign

0.041

Sift

Benign

0.19

Sift4G

Benign

0.26

Vest4

0.24

MutPred

0.37

Gain of relative solvent accessibility (P = 0.0166)

MVP

0.18

MPC

1.1

ClinPred

0.94

GERP RS

4.5

PromoterAI

0.0072

Neutral

(source)

Varity_R

0.041

gMVP

0.051

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over