6-96976146-C-G

Variant names:

• chr6-96976146-C-G
• NM_052904.4:c.173C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_052904.4(KLHL32):​c.173C>G​(p.Ala58Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KLHL32 NM_052904.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL32	NM_052904.4	c.173C>G	p.Ala58Gly	missense_variant	Exon 3 of 11	ENST00000369261.9	NP_443136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL32	ENST00000369261.9	c.173C>G	p.Ala58Gly	missense_variant	Exon 3 of 11	2	NM_052904.4	ENSP00000358265.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435622 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

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

Jul 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173C>G (p.A58G) alteration is located in exon 3 (coding exon 2) of the KLHL32 gene. This alteration results from a C to G substitution at nucleotide position 173, causing the alanine (A) at amino acid position 58 to be replaced by a glycine (G). 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	0.58
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.1	M;M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.065	T;T;T;T
Sift4G	Benign	0.29	T;T;T;D
Polyphen		1.0	.;.;D;.
Vest4		0.75
MutPred		0.68		Loss of catalytic residue at A58 (P = 0.0765);Loss of catalytic residue at A58 (P = 0.0765);Loss of catalytic residue at A58 (P = 0.0765);Loss of catalytic residue at A58 (P = 0.0765);
MVP		0.69
MPC		1.2
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.33
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-97424022;