NM_018316.3:c.223C>G

Variant names:

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

Variant summary

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

The NM_018316.3(KLHL26):​c.223C>G​(p.Pro75Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. P75T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHL26 NM_018316.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• Publications: 0 publications found

Genes affected

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

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=0.35863888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL26	NM_018316.3	c.223C>G	p.Pro75Ala	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>G	p.Pro75Ala	missense_variant	Exon 2 of 3	1	NM_018316.3	ENSP00000300976.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451506 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721422

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

American (AMR) AF: 0.00 AC: 0 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: 9.03e-7 AC: 1 AN: 1107980

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Uncertain	0.54	D;D;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.11
Sift	Benign	0.11	T;.;.
Sift4G	Benign	0.83	T;T;T
Polyphen		0.013	B;.;.
Vest4		0.22
MutPred		0.46		Loss of methylation at K78 (P = 0.0647);Loss of methylation at K78 (P = 0.0647);Loss of methylation at K78 (P = 0.0647);
MVP		0.82
MPC		0.57
ClinPred		0.30	T
GERP RS		4.1
Varity_R		0.080
gMVP		0.17
Mutation Taster		=81/19	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;