3-42691889-G-C

Variant names:

• chr3-42691889-G-C
• rs201856772
• NM_152393.4:c.1762G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152393.4(KLHL40):​c.1762G>C​(p.Glu588Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E588K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41
• Publications: 3 publications found

Genes affected

KLHL40 (HGNC:30372): (kelch like family member 40) This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]

KLHL40 Gene-Disease associations (from GenCC):

• nemaline myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.355601).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152393.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	NM_152393.4	MANE Select	c.1762G>C	p.Glu588Gln	missense	Exon 6 of 6	NP_689606.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1762G>C	p.Glu588Gln	missense	Exon 6 of 6	ENSP00000287777.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.45
Sift	Benign	0.045	D
Sift4G	Benign	0.074	T
Polyphen		0.95	P
Vest4		0.23
MutPred		0.52		Loss of disorder (P = 0.0834)
MVP		0.87
MPC		0.16
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.35
gMVP		0.56
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201856772; hg19: chr3-42733381;