chr17-41226920-C-T

Variant names:

• chr17-41226920-C-T
• rs143324960
• NM_031961.3:c.266C>T

Variant summary

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

The NM_031961.3(KRTAP9-2):​c.266C>T​(p.Thr89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP9-2 NM_031961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.878
• Publications: 1 publications found

Genes affected

KRTAP9-2 (HGNC:16926): (keratin associated protein 9-2) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.088713825).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031961.3. 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
	KRTAP9-2	NM_031961.3	MANE Select	c.266C>T	p.Thr89Ile	missense	Exon 1 of 1	NP_114167.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-2	ENST00000377721.3	TSL:6 MANE Select	c.266C>T	p.Thr89Ile	missense	Exon 1 of 1	ENSP00000366950.3	Q9BYQ4

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 54 AN: 146210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000744

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000274

Gnomad ASJ AF: 0.000297

Gnomad EAS AF: 0.000400

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000610

Gnomad OTH AF: 0.00101

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250676 AF XY: 0.0000369

Gnomad AFR exome AF: 0.0000627

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: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000123 AC: 18 AN: 1461242 Hom.: 0 Cov.: 208 AF XY: 0.00000825 AC XY: 6 AN XY: 726932

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

African (AFR) AF: 0.0000599 AC: 2 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44676

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111658

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000134017), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000376 AC: 55 AN: 146312 Hom.: 0 Cov.: 32 AF XY: 0.000534 AC XY: 38 AN XY: 71104

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

African (AFR) AF: 0.0000742 AC: 3 AN: 40418

American (AMR) AF: 0.000274 AC: 4 AN: 14594

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 1 AN: 3366

East Asian (EAS) AF: 0.000602 AC: 3 AN: 4986

South Asian (SAS) AF: 0.000440 AC: 2 AN: 4542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000611 AC: 40 AN: 65518

Other (OTH) AF: 0.000997 AC: 2 AN: 2006

⚠️ 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.

Alfa AF: 0.00674 Hom.: 0

ExAC AF: 0.0000412 AC: 5

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	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.6
DANN	Benign	0.81
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.055	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.88
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.029
Sift	Benign	0.085	T
Sift4G	Benign	0.066	T
Polyphen		0.48	P
Vest4		0.063
MutPred		0.42		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.10
MPC		1.2
ClinPred		0.14	T
GERP RS		1.3
PromoterAI		0.0066	Neutral
Varity_R		0.14
gMVP		0.074
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143324960; hg19: chr17-39383172; COSMIC: COSV66646667;