19-18637135-C-G

Position:

• chr19-18637135-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018316.3(KLHL26):​c.81C>G​(p.Asn27Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLHL26 NM_018316.3 missense, splice_region
• Scores: Splicing: ADA: 0.008610
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.373

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08468157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL26	NM_018316.3	c.81C>G	p.Asn27Lys	missense_variant, splice_region_variant	1/3	ENST00000300976.9	NP_060786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL26	ENST00000300976.9	c.81C>G	p.Asn27Lys	missense_variant, splice_region_variant	1/3	1	NM_018316.3	ENSP00000300976	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1187900 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 573260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.81C>G (p.N27K) alteration is located in exon 1 (coding exon 1) of the KLHL26 gene. This alteration results from a C to G substitution at nucleotide position 81, causing the asparagine (N) at amino acid position 27 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.36	T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.48	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.23	T;.;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.077
MutPred		0.23		Gain of ubiquitination at N27 (P = 0.0045);Gain of ubiquitination at N27 (P = 0.0045);Gain of ubiquitination at N27 (P = 0.0045);
MVP		0.72
MPC		0.67
ClinPred		0.16	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0086
dbscSNV1_RF	Benign	0.15
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18747945;