Variant 21-44666807-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181684.3(KRTAP12-2):c.80C>T(p.Pro27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,611,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KRTAP12-2
NM_181684.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.940

Variant links:

Genes affected

KRTAP12-2 (HGNC:20530): (keratin associated protein 12-2) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP12-2 links:

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

TSPEAR links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13980335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP12-2	NM_181684.3 linkuse as main transcript	c.80C>T	p.Pro27Leu	missense_variant	1/1	ENST00000360770.3	NP_859012.1	P59991
TSPEAR	NM_144991.3 linkuse as main transcript	c.82+44626C>T		intron_variant		ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 linkuse as main transcript	c.-123+23738C>T		intron_variant			NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRTAP12-2	ENST00000360770.3 linkuse as main transcript	c.80C>T	p.Pro27Leu	missense_variant	1/1	6	NM_181684.3	ENSP00000354001.3	P59991
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.82+44626C>T		intron_variant		1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.*27+23738C>T		intron_variant				ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249090

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1459546

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

725982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.80C>T (p.P27L) alteration is located in exon 1 (coding exon 1) of the KRTAP12-2 gene. This alteration results from a C to T substitution at nucleotide position 80, causing the proline (P) at amino acid position 27 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.71

M_CAP

Benign

0.0010

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.095

Sift

Benign

0.033

Sift4G

Uncertain

0.0040

Polyphen

0.12

Vest4

0.11

MutPred

0.61

Loss of loop (P = 0.0112);

MVP

0.34

MPC

0.19

ClinPred

0.31

GERP RS

1.5

Varity_R

0.093

gMVP

0.059

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over