3-42691888-CGAG-C

Variant names:

• chr3-42691888-CGAG-C
• rs142843476
• NM_152393.4:c.1768_1770delGAG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_152393.4(KLHL40):​c.1768_1770delGAG​(p.Glu590del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,603,008 control chromosomes in the GnomAD database, including 95 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (39 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (56 hom.)
• Consequence: KLHL40 NM_152393.4 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.88
• 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: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_152393.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-42691888-CGAG-C is Benign according to our data. Variant chr3-42691888-CGAG-C is described in ClinVar as Benign. ClinVar VariationId is 262643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

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_1770delGAG	p.Glu590del	conservative_inframe_deletion	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_1770delGAG	p.Glu590del	conservative_inframe_deletion	Exon 6 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1753_1755delGAG	p.Glu585del	conservative_inframe_deletion	Exon 6 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1747_1749delGAG	p.Glu583del	conservative_inframe_deletion	Exon 6 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2346 AN: 152104 Hom.: 39 Cov.: 31

Gnomad AFR AF: 0.0528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00443 AC: 1109 AN: 250158 AF XY: 0.00319

Gnomad AFR exome AF: 0.0576

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00166 AC: 2409 AN: 1450786 Hom.: 56 AF XY: 0.00136 AC XY: 983 AN XY: 722512

African (AFR) AF: 0.0542 AC: 1799 AN: 33222

American (AMR) AF: 0.00391 AC: 175 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5738

European-Non Finnish (NFE) AF: 0.000155 AC: 171 AN: 1101940

Other (OTH) AF: 0.00390 AC: 234 AN: 60038

GnomAD4 genome AF: 0.0154 AC: 2348 AN: 152222 Hom.: 39 Cov.: 31 AF XY: 0.0150 AC XY: 1119 AN XY: 74430

African (AFR) AF: 0.0527 AC: 2188 AN: 41518

American (AMR) AF: 0.00692 AC: 106 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68006

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00200 Hom.: 4

Bravo AF: 0.0179

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 8 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=49/51	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: rs142843476; hg19: chr3-42733380; COSMIC: COSV55134424; COSMIC: COSV55134424;