21-44666549-A-T

Variant names:

• chr21-44666549-A-T
• rs782218290
• NM_181684.3:c.338T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181684.3(KRTAP12-2):​c.338T>A​(p.Val113Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 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: 0.0000027 (0 hom.)
• Consequence: KRTAP12-2 NM_181684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.567
• Publications: 0 publications found

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]

TSPEAR Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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=0.23701221).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181684.3. 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
	KRTAP12-2	NM_181684.3	MANE Select	c.338T>A	p.Val113Asp	missense	Exon 1 of 1	NP_859012.1	P59991
	TSPEAR	NM_144991.3	MANE Select	c.82+44884T>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+23996T>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP12-2	ENST00000360770.3	TSL:6 MANE Select	c.338T>A	p.Val113Asp	missense	Exon 1 of 1	ENSP00000354001.3	P59991
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+44884T>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+44884T>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 249162 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460984 Hom.: 0 Cov.: 102 AF XY: 0.00000275 AC XY: 2 AN XY: 726828

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111334

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.57
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.052
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.27
MutPred		0.42		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.31
MPC		0.94
ClinPred		0.36	T
GERP RS		-2.5
PromoterAI		0.076	Neutral
Varity_R		0.57
gMVP		0.045
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782218290; hg19: chr21-46086466;