chr6-96976146-C-G

Variant names:

• chr6-96976146-C-G
• rs1775666947
• NM_052904.4:c.173C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A58V) has been classified 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
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052904.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL32	NM_052904.4	MANE Select	c.173C>G	p.Ala58Gly	missense	Exon 3 of 11	NP_443136.2	Q96NJ5-1
	KLHL32	NM_001323252.2		c.173C>G	p.Ala58Gly	missense	Exon 4 of 12	NP_001310181.1	Q96NJ5-1
	KLHL32	NM_001286250.2		c.173C>G	p.Ala58Gly	missense	Exon 3 of 10	NP_001273179.1	Q96NJ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL32	ENST00000369261.9	TSL:2 MANE Select	c.173C>G	p.Ala58Gly	missense	Exon 3 of 11	ENSP00000358265.4	Q96NJ5-1
	KLHL32	ENST00000951639.1		c.173C>G	p.Ala58Gly	missense	Exon 4 of 12	ENSP00000621698.1
	KLHL32	ENST00000536676.5	TSL:2	c.173C>G	p.Ala58Gly	missense	Exon 3 of 10	ENSP00000440382.1	Q96NJ5-2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32764

American (AMR) AF: 0.00 AC: 0 AN: 42504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38694

South Asian (SAS) AF: 0.00 AC: 0 AN: 83714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094454

Other (OTH) AF: 0.00 AC: 0 AN: 59126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.49
Sift	Benign	0.065	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.68		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
Mutation Taster		=39/61	disease causing

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: rs1775666947; hg19: chr6-97424022;