6-96976037-G-A

Variant summary

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

The NM_052904.4(KLHL32):c.64G>A(p.Glu22Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000832 in 1,442,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000083 (0 hom.)
• Consequence: KLHL32 NM_052904.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

Genes affected

KLHL32 (HGNC:21221): (kelch like family member 32)

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=0.11236557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL32	NM_052904.4	c.64G>A	p.Glu22Lys	missense_variant	3/11	ENST00000369261.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL32	ENST00000369261.9	c.64G>A	p.Glu22Lys	missense_variant	3/11	2	NM_052904.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246026 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132968

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000832 AC: 12 AN: 1442620 Hom.: 0 Cov.: 31 AF XY: 0.00000700 AC XY: 5 AN XY: 714124

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000729

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

May 16, 2023

The c.64G>A (p.E22K) alteration is located in exon 3 (coding exon 2) of the KLHL32 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the glutamic acid (E) at amino acid position 22 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	0.066
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	23
Dann	Benign	0.96
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.20	N;N;N;.
MutationTaster	Benign	0.84	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.32	N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.44	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.24
MutPred		0.38		Gain of ubiquitination at E22 (P = 0.0077);Gain of ubiquitination at E22 (P = 0.0077);Gain of ubiquitination at E22 (P = 0.0077);Gain of ubiquitination at E22 (P = 0.0077);
MVP		0.48
MPC		0.44
ClinPred		0.46	T
GERP RS		5.1
Varity_R		0.077
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757037434; hg19: chr6-97423913; COSMIC: COSV65110843;