chr19-18664400-C-A

Variant names:

• chr19-18664400-C-A
• rs776021047
• NM_018316.3:c.223C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_018316.3(KLHL26):​c.223C>A​(p.Pro75Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000689 in 1,451,506 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: KLHL26 NM_018316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65
• Publications: 0 publications found

Genes affected

KLHL26 (HGNC:25623): (kelch like family member 26)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3385941).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL26	NM_018316.3	c.223C>A	p.Pro75Thr	missense_variant	Exon 2 of 3	ENST00000300976.9	NP_060786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL26	ENST00000300976.9	c.223C>A	p.Pro75Thr	missense_variant	Exon 2 of 3	1	NM_018316.3	ENSP00000300976.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000366 AC: 9 AN: 245778 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451506 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721422

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.000226 AC: 10 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107980

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223C>A (p.P75T) alteration is located in exon 2 (coding exon 2) of the KLHL26 gene. This alteration results from a C to A substitution at nucleotide position 223, causing the proline (P) at amino acid position 75 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;.;.
Sift4G	Benign	0.53	T;T;T
Polyphen		0.25	B;.;.
Vest4		0.17
MutPred		0.48		Loss of methylation at K78 (P = 0.0745);Loss of methylation at K78 (P = 0.0745);Loss of methylation at K78 (P = 0.0745);
MVP		0.81
MPC		0.70
ClinPred		0.17	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.22
Mutation Taster		=83/17	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: rs776021047; hg19: chr19-18775210;