chr19-18667802-C-G

Variant names:

• chr19-18667802-C-G
• NM_018316.3:c.405C>G

Variant summary

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

The NM_018316.3(KLHL26):​c.405C>G​(p.Asp135Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KLHL26 NM_018316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.68
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL26	NM_018316.3	c.405C>G	p.Asp135Glu	missense_variant	Exon 3 of 3	ENST00000300976.9	NP_060786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL26	ENST00000300976.9	c.405C>G	p.Asp135Glu	missense_variant	Exon 3 of 3	1	NM_018316.3	ENSP00000300976.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.405C>G (p.D135E) alteration is located in exon 3 (coding exon 3) of the KLHL26 gene. This alteration results from a C to G substitution at nucleotide position 405, causing the aspartic acid (D) at amino acid position 135 to be replaced by a glutamic acid (E). 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	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	4.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.97	L;.
PhyloP100		-1.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.10	T;T
Polyphen		0.99	D;.
Vest4		0.81
MutPred		0.48		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.84
MPC		1.5
ClinPred		0.91	D
GERP RS		-7.4
Varity_R		0.29
gMVP		0.50
Mutation Taster		=60/40	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

hg19: chr19-18778612;