21-44591869-G-C

Variant names:

• chr21-44591869-G-C
• rs1196797350
• NM_198688.3:c.616C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_198688.3(KRTAP10-6):​c.616C>G​(p.Pro206Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• Publications: 0 publications found

Genes affected

KRTAP10-6 (HGNC:20523): (keratin associated protein 10-6) 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13419372).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198688.3. 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
	KRTAP10-6	NM_198688.3	MANE Select	c.616C>G	p.Pro206Ala	missense	Exon 1 of 1	NP_941961.3	P60371
	TSPEAR	NM_144991.3	MANE Select	c.83-23864C>G		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-23864C>G		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-6	ENST00000400368.1	TSL:6 MANE Select	c.616C>G	p.Pro206Ala	missense	Exon 1 of 1	ENSP00000383219.1	P60371
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-23864C>G		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-23864C>G		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00000746 AC: 1 AN: 134130 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000335

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1456896 Hom.: 0 Cov.: 132 AF XY: 0.00 AC XY: 0 AN XY: 724866

African (AFR) AF: 0.00 AC: 0 AN: 31800

American (AMR) AF: 0.00 AC: 0 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 38572

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111228

Other (OTH) AF: 0.00 AC: 0 AN: 59978

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000745 AC: 1 AN: 134204 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 65134

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000334 AC: 1 AN: 29958

American (AMR) AF: 0.00 AC: 0 AN: 12904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4552

South Asian (SAS) AF: 0.00 AC: 0 AN: 4498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66544

Other (OTH) AF: 0.00 AC: 0 AN: 1892

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
CADD	Benign	7.3
MetaRNN	Benign	0.13	T
PhyloP100		-0.61
PROVEAN	Uncertain	-2.5	D
Sift	Benign	0.095	T
Sift4G	Benign	0.061	T
Vest4		0.12
gMVP		0.025

Splicing

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

Other links and lift over

dbSNP: rs1196797350;