17-41046978-G-A

Variant names:

• chr17-41046978-G-A
• rs1439869821
• NM_001123387.1:c.290C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001123387.1(KRTAP2-1):​c.290C>T​(p.Thr97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. T97N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000058 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP2-1 NM_001123387.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

KRTAP2-1 (HGNC:16775): (keratin associated protein 2-1) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000306126 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2443957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001123387.1. 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
	KRTAP2-1	NM_001123387.1	MANE Select	c.290C>T	p.Thr97Ile	missense	Exon 1 of 1	NP_001116859.1	Q9BYU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP2-1	ENST00000391419.3	TSL:6 MANE Select	c.290C>T	p.Thr97Ile	missense	Exon 1 of 1	ENSP00000375238.3	Q9BYU5
	ENSG00000306126	ENST00000815517.1		n.220-13321G>A		intron	N/A
	ENSG00000306126	ENST00000815518.1		n.160-13321G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000578 AC: 8 AN: 1383874 Hom.: 0 Cov.: 33 AF XY: 0.00000732 AC XY: 5 AN XY: 682838

⚠️ 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: 31544

American (AMR) AF: 0.00 AC: 0 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.00 AC: 0 AN: 35780

South Asian (SAS) AF: 0.00 AC: 0 AN: 79042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36424

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4064

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078532

Other (OTH) AF: 0.00 AC: 0 AN: 57728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0077	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.45		Gain of catalytic residue at T97 (P = 0.1731)
MVP		0.22
ClinPred		0.95	D
GERP RS		5.8
PromoterAI		0.020	Neutral
Varity_R		0.17
gMVP		0.14

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: rs1439869821; hg19: chr17-39203230;