21-44550948-C-A

Variant names:

• chr21-44550948-C-A
• NM_198693.4:c.511G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198693.4(KRTAP10-2):​c.511G>T​(p.Ala171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: KRTAP10-2 NM_198693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018960238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-2	NM_198693.4	c.511G>T	p.Ala171Ser	missense_variant	Exon 1 of 1	ENST00000391621.1	NP_941966.1
TSPEAR	NM_144991.3	c.303+16837G>T		intron_variant	Intron 2 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.99+16837G>T		intron_variant	Intron 3 of 12		NP_001258966.1
KRTAP10-2	NR_130165.2	n.127-274G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-2	ENST00000391621.1	c.511G>T	p.Ala171Ser	missense_variant	Exon 1 of 1	6	NM_198693.4	ENSP00000375479.1
TSPEAR	ENST00000323084.9	c.303+16837G>T		intron_variant	Intron 2 of 11	1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 162

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.511G>T (p.A171S) alteration is located in exon 1 (coding exon 1) of the KRTAP10-2 gene. This alteration results from a G to T substitution at nucleotide position 511, causing the alanine (A) at amino acid position 171 to be replaced by a serine (S). 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	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.10
DANN	Benign	0.82
DEOGEN2	Benign	0.00021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.28	N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.020
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.044
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.030
MPC		0.052
ClinPred		0.043	T
GERP RS		0.36
Varity_R		0.062
gMVP		0.023

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45970831;