chr21-44666856-G-T

Variant names:

• chr21-44666856-G-T
• rs781876751
• NM_181684.3:c.31C>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.31C>A​(p.Gln11Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP12-2 NM_181684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.537
• Publications: 1 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=0.13662666).

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.31C>A	p.Gln11Lys	missense	Exon 1 of 1	NP_859012.1	P59991
	TSPEAR	NM_144991.3	MANE Select	c.82+44577C>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+23689C>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.31C>A	p.Gln11Lys	missense	Exon 1 of 1	ENSP00000354001.3	P59991
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+44577C>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+44577C>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461380 Hom.: 0 Cov.: 61 AF XY: 0.00000138 AC XY: 1 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111740

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.54
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.045
Sift	Benign	0.59	T
Sift4G	Benign	0.45	T
Polyphen		0.41	B
Vest4		0.35
MutPred		0.38		Gain of methylation at Q11 (P = 1e-04)
MVP		0.35
MPC		0.24
ClinPred		0.27	T
GERP RS		2.7
PromoterAI		-0.027	Neutral
Varity_R		0.19
gMVP		0.060
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs781876751; hg19: chr21-46086773;