chr17-41065478-C-T

Variant names:

• chr17-41065478-C-T
• rs776346638
• NM_033184.4:c.368G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033184.4(KRTAP2-4):​c.368G>A​(p.Cys123Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000489 in 1,432,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: KRTAP2-4 NM_033184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• Publications: 0 publications found

Genes affected

KRTAP2-4 (HGNC:18891): (keratin associated protein 2-4) 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 high 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033184.4. 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
	KRTAP2-4	NM_033184.4	MANE Select	c.368G>A	p.Cys123Tyr	missense	Exon 1 of 1	NP_149440.1	Q9BYR9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP2-4	ENST00000394015.3	TSL:6 MANE Select	c.368G>A	p.Cys123Tyr	missense	Exon 1 of 1	ENSP00000377583.2	Q9BYR9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000509 AC: 1 AN: 196438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000489 AC: 7 AN: 1432238 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 709146

African (AFR) AF: 0.00 AC: 0 AN: 33208

American (AMR) AF: 0.00 AC: 0 AN: 39416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25408

East Asian (EAS) AF: 0.00 AC: 0 AN: 38892

South Asian (SAS) AF: 0.00 AC: 0 AN: 81874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000637 AC: 7 AN: 1098302

Other (OTH) AF: 0.00 AC: 0 AN: 59434

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000848 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.019	T
PhyloP100		4.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.85
MVP		0.18
MPC		0.97
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		0.0051	Neutral
Varity_R		0.92
gMVP		0.17
Mutation Taster		=72/28	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: rs776346638; hg19: chr17-39221730; COSMIC: COSV101224322;