3-42691888-CGAG-CGAGGAG

Variant names:

• chr3-42691888-C-CGAG
• rs142843476
• NM_152393.4:c.1768_1770dupGAG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_152393.4(KLHL40):​c.1768_1770dupGAG​(p.Glu590dup) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL40 NM_152393.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_152393.4. Strenght limited to Supporting due to length of the change: 1aa.

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.1768_1770dupGAG	p.Glu590dup	conservative_inframe_insertion	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.1768_1770dupGAG	p.Glu590dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1753_1755dupGAG	p.Glu585dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1747_1749dupGAG	p.Glu583dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142843476; hg19: chr3-42733380;