21-44551235-C-T

Position:

• chr21-44551235-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198693.4(KRTAP10-2):​c.224G>A​(p.Cys75Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRTAP10-2 NM_198693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

KRTAP10-2 (HGNC:22967): (keratin associated protein 10-2) This gene encodes a member of the high sulfur-type keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. This gene is located in a cluster of similar genes on 21q22.3. Alternatively-spliced transcript variants have been identified. [provided by RefSeq, Jan 2015]

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-2	NM_198693.4	c.224G>A	p.Cys75Tyr	missense_variant	1/1	ENST00000391621.1	NP_941966.1
TSPEAR	NM_144991.3	c.303+16550G>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.99+16550G>A		intron_variant			NP_001258966.1
KRTAP10-2	NR_130165.2	n.126+145G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-2	ENST00000391621.1	c.224G>A	p.Cys75Tyr	missense_variant	1/1	6	NM_198693.4	ENSP00000375479.1
TSPEAR	ENST00000323084.9	c.303+16550G>A		intron_variant		1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461644 Hom.: 0 Cov.: 182 AF XY: 0.00 AC XY: 0 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.224G>A (p.C75Y) alteration is located in exon 1 (coding exon 1) of the KRTAP10-2 gene. This alteration results from a G to A substitution at nucleotide position 224, causing the cysteine (C) at amino acid position 75 to be replaced by a tyrosine (Y). 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	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.61
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0044	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.71		Gain of glycosylation at T72 (P = 0.0704);
MVP		0.061
MPC		0.089
ClinPred		0.59	D
GERP RS		2.4
Varity_R		0.90
gMVP		0.096

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

Publications

LitVar

Other links and lift over

dbSNP: rs2053426433; hg19: chr21-45971118;