6-96976146-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_052904.4(KLHL32):​c.173C>T​(p.Ala58Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A58G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

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>T	p.Ala58Val	missense	Exon 3 of 11	NP_443136.2	Q96NJ5-1
	KLHL32	NM_001323252.2		c.173C>T	p.Ala58Val	missense	Exon 4 of 12	NP_001310181.1	Q96NJ5-1
	KLHL32	NM_001286250.2		c.173C>T	p.Ala58Val	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>T	p.Ala58Val	missense	Exon 3 of 11	ENSP00000358265.4	Q96NJ5-1
	KLHL32	ENST00000951639.1		c.173C>T	p.Ala58Val	missense	Exon 4 of 12	ENSP00000621698.1
	KLHL32	ENST00000536676.5	TSL:2	c.173C>T	p.Ala58Val	missense	Exon 3 of 10	ENSP00000440382.1	Q96NJ5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.38	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.35
Sift	Benign	0.60	T
Sift4G	Benign	0.069	T
Polyphen		0.56	P
Vest4		0.83
MutPred		0.64		Gain of methylation at K57 (P = 0.04)
MVP		0.69
MPC		1.2
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.24
gMVP		0.46
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -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;