17-41226911-G-C

Variant names:

• chr17-41226911-G-C
• rs200569975
• NM_031961.3:c.257G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031961.3(KRTAP9-2):​c.257G>C​(p.Cys86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. C86Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRTAP9-2 NM_031961.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.302862).

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.257G>C	p.Cys86Ser	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.257G>C	p.Cys86Ser	missense	Exon 1 of 1	ENSP00000366950.3	Q9BYQ4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 207 AF XY: 0.00 AC XY: 0 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.0
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.76	P
Vest4		0.16
MutPred		0.70		Gain of relative solvent accessibility (P = 0.0483)
MVP		0.27
MPC		1.4
ClinPred		0.95	D
GERP RS		3.5
PromoterAI		0.0030	Neutral
Varity_R		0.71
gMVP		0.14
Mutation Taster		=41/59	disease causing

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: rs200569975; hg19: chr17-39383163;