chr3-42691919-C-G

Variant names:

• chr3-42691919-C-G
• rs767572121
• NM_152393.4:c.1792C>G

Variant summary

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

The NM_152393.4(KLHL40):​c.1792C>G​(p.Arg598Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R598Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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=0.28410774).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	NM_152393.4	MANE Select	c.1792C>G	p.Arg598Gly	missense	Exon 6 of 6	NP_689606.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1792C>G	p.Arg598Gly	missense	Exon 6 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1777C>G	p.Arg593Gly	missense	Exon 6 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1771C>G	p.Arg591Gly	missense	Exon 6 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.29
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.42
Sift	Benign	0.067	T
Sift4G	Uncertain	0.058	T
Polyphen		0.15	B
Vest4		0.63
MutPred		0.52		Loss of solvent accessibility (P = 0.1235)
MVP		0.54
MPC		0.13
ClinPred		0.86	D
GERP RS		3.3
Varity_R		0.47
gMVP		0.58
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs767572121; hg19: chr3-42733411; COSMIC: COSV99825671; COSMIC: COSV99825671;