17-41047021-A-T

Variant names:

• chr17-41047021-A-T
• rs986449218
• NM_001123387.1:c.247T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001123387.1(KRTAP2-1):​c.247T>A​(p.Ser83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000507 in 1,500,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. S83L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: KRTAP2-1 NM_001123387.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10257915).

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.247T>A	p.Ser83Thr	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.247T>A	p.Ser83Thr	missense	Exon 1 of 1	ENSP00000375238.3	Q9BYU5
	ENSG00000306126	ENST00000815517.1		n.220-13278A>T		intron	N/A
	ENSG00000306126	ENST00000815518.1		n.160-13278A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000155 AC: 2 AN: 129342 AF XY: 0.0000143

Gnomad AFR exome AF: 0.000151

Gnomad AMR exome AF: 0.0000417

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: 0.0000237 AC: 32 AN: 1348060 Hom.: 0 Cov.: 30 AF XY: 0.0000196 AC XY: 13 AN XY: 664942

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

African (AFR) AF: 0.000357 AC: 11 AN: 30816

American (AMR) AF: 0.000230 AC: 8 AN: 34844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35432

South Asian (SAS) AF: 0.00 AC: 0 AN: 76698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3954

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1052204

Other (OTH) AF: 0.000231 AC: 13 AN: 56378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000105804), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152010 Hom.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 30 AN XY: 74230

African (AFR) AF: 0.000483 AC: 20 AN: 41404

American (AMR) AF: 0.00144 AC: 22 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00 Hom.: 0

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	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0058	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.40	T
Polyphen		0.60	P
Vest4		0.35
MutPred		0.43		Gain of glycosylation at S82 (P = 0.0704)
MVP		0.088
ClinPred		0.25	T
GERP RS		5.8
PromoterAI		0.0037	Neutral
Varity_R		0.14
gMVP		0.053
Mutation Taster		=99/1	polymorphism

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: rs986449218; hg19: chr17-39203273;