21-44666856-G-A

Variant names:

• chr21-44666856-G-A
• rs781876751
• NM_181684.3:c.31C>T

Variant summary

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

The NM_181684.3(KRTAP12-2):​c.31C>T​(p.Gln11*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KRTAP12-2 NM_181684.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

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

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>T	p.Gln11*	stop_gained	Exon 1 of 1	NP_859012.1	P59991
	TSPEAR	NM_144991.3	MANE Select	c.82+44577C>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+23689C>T		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>T	p.Gln11*	stop_gained	Exon 1 of 1	ENSP00000354001.3	P59991
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+44577C>T		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+44577C>T		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: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000323 AC: 8 AN: 247984 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 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: 0.000179 AC: 8 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: 0.00000656 AC: 1 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.44	N
PhyloP100		0.54
Vest4		0.063
GERP RS		2.7
PromoterAI		-0.028	Neutral
Mutation Taster		=175/25	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;