chr21-30319605-C-T

Variant names:

• chr21-30319605-C-T
• rs767826058
• NM_203405.2:c.431G>A

Variant summary

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

The NM_203405.2(KRTAP26-1):​c.431G>A​(p.Arg144His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R144C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: KRTAP26-1 NM_203405.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0130
• Publications: 4 publications found

Genes affected

KRTAP26-1 (HGNC:33760): (keratin associated protein 26-1) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.41370985).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203405.2. 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
	KRTAP26-1	NM_203405.2	MANE Select	c.431G>A	p.Arg144His	missense	Exon 1 of 1	NP_981950.1	Q6PEX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP26-1	ENST00000360542.5	TSL:6 MANE Select	c.431G>A	p.Arg144His	missense	Exon 1 of 1	ENSP00000353742.3	Q6PEX3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151754 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 14 AN: 250900 AF XY: 0.0000590

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111918

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151754 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74066

African (AFR) AF: 0.0000485 AC: 2 AN: 41276

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000412 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	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.013
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.073
Sift	Benign	0.25	T
Sift4G	Benign	0.10	T
Polyphen		0.79	P
Vest4		0.20
MutPred		0.83		Loss of loop (P = 0.0203)
MVP		0.36
MPC		0.20
ClinPred		0.046	T
GERP RS		2.9
Varity_R		0.030
gMVP		0.14
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs767826058; hg19: chr21-31691923; COSMIC: COSV62128671;