chr21-44666799-A-G

Position:

• chr21-44666799-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181684.3(KRTAP12-2):​c.88T>C​(p.Cys30Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP12-2 NM_181684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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]

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP12-2	NM_181684.3	c.88T>C	p.Cys30Arg	missense_variant	1/1	ENST00000360770.3	NP_859012.1
TSPEAR	NM_144991.3	c.82+44634T>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+23746T>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP12-2	ENST00000360770.3	c.88T>C	p.Cys30Arg	missense_variant	1/1	6	NM_181684.3	ENSP00000354001.3
TSPEAR	ENST00000323084.9	c.82+44634T>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+23746T>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 106

GnomAD4 genome Cov.: 33

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

Jan 10, 2022

The c.88T>C (p.C30R) alteration is located in exon 1 (coding exon 1) of the KRTAP12-2 gene. This alteration results from a T to C substitution at nucleotide position 88, causing the cysteine (C) at amino acid position 30 to be replaced by an arginine (R). 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	0.32
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0033	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.099
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.46		Gain of solvent accessibility (P = 1e-04);
MVP		0.49
MPC		0.34
ClinPred		0.95	D
GERP RS		2.2
Varity_R		0.58
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46086716;