NM_033184.4:c.240C>G

Variant names:

• chr17-41065606-G-C
• rs768531527
• NM_033184.4:c.240C>G

Variant summary

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

The NM_033184.4(KRTAP2-4):​c.240C>G​(p.Cys80Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000864 in 150,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. C80S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP2-4 NM_033184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4022278).

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.240C>G	p.Cys80Trp	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.240C>G	p.Cys80Trp	missense	Exon 1 of 1	ENSP00000377583.2	Q9BYR9

Frequencies

GnomAD3 genomes AF: 0.0000865 AC: 13 AN: 150346 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000243

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: 0.000190

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000306 AC: 4 AN: 130616 AF XY: 0.0000284

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: 0.000190

Gnomad NFE exome AF: 0.0000594

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000441 AC: 6 AN: 1361290 Hom.: 0 Cov.: 30 AF XY: 0.00000299 AC XY: 2 AN XY: 669438

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

African (AFR) AF: 0.00 AC: 0 AN: 31176

American (AMR) AF: 0.00 AC: 0 AN: 35118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24628

East Asian (EAS) AF: 0.00 AC: 0 AN: 35410

South Asian (SAS) AF: 0.0000255 AC: 2 AN: 78366

European-Finnish (FIN) AF: 0.0000883 AC: 3 AN: 33966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061742

Other (OTH) AF: 0.00 AC: 0 AN: 56842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000277556), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000864 AC: 13 AN: 150464 Hom.: 0 Cov.: 30 AF XY: 0.0000952 AC XY: 7 AN XY: 73534

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

African (AFR) AF: 0.0000243 AC: 1 AN: 41220

American (AMR) AF: 0.00 AC: 0 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10506

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67092

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ 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: 0.000671 Hom.: 0

ExAC AF: 0.0000913 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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.16	D
PhyloP100		4.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.021	D
Vest4		0.55
MVP		0.25
MPC		1.8
ClinPred		0.79	D
GERP RS		5.5
PromoterAI		0.0098	Neutral
Varity_R		0.57
gMVP		0.11
Mutation Taster		=53/47	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: rs768531527; hg19: chr17-39221858;