chr17-41178058-C-G

Variant names:

• chr17-41178058-C-G
• rs773898116
• NM_033062.4:c.107G>C

Variant summary

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

The NM_033062.4(KRTAP4-2):​c.107G>C​(p.Cys36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C36F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KRTAP4-2 NM_033062.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

Genes affected

KRTAP4-2 (HGNC:18900): (keratin associated protein 4-2) 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 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033062.4. 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
	KRTAP4-2	NM_033062.4	MANE Select	c.107G>C	p.Cys36Ser	missense	Exon 1 of 1	NP_149051.2	Q9BYR5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-2	ENST00000377726.3	TSL:6 MANE Select	c.107G>C	p.Cys36Ser	missense	Exon 1 of 1	ENSP00000366955.2	Q9BYR5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000411 AC: 6 AN: 1461194 Hom.: 0 Cov.: 175 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000450 AC: 2 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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	0.31
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.0000038
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0040	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.2
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		0.41	B
Vest4		0.26
MutPred		0.71		Gain of relative solvent accessibility (P = 0.09)
MVP		0.41
MPC		0.11
ClinPred		0.53	D
GERP RS		4.3
PromoterAI		-0.0042	Neutral
Varity_R		0.60
gMVP		0.22
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs773898116; hg19: chr17-39334310;