NM_152393.4:c.6G>T

Variant names:

• chr3-42685624-G-T
• rs562643282
• NM_152393.4:c.6G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_152393.4(KLHL40):​c.6G>T​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,592,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: KLHL40 NM_152393.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.182
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-42685624-G-T is Benign according to our data. Variant chr3-42685624-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2768064.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.182 with no splicing effect.

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.6G>T	p.Ala2Ala	synonymous	Exon 1 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.6G>T	p.Ala2Ala	synonymous	Exon 1 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.6G>T	p.Ala2Ala	synonymous	Exon 1 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.6G>T	p.Ala2Ala	synonymous	Exon 1 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000139 AC: 3 AN: 216278 AF XY: 0.00000851

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 32 AN: 1440598 Hom.: 0 Cov.: 30 AF XY: 0.0000266 AC XY: 19 AN XY: 714744

African (AFR) AF: 0.0000304 AC: 1 AN: 32874

American (AMR) AF: 0.00 AC: 0 AN: 42422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 38252

South Asian (SAS) AF: 0.00 AC: 0 AN: 83474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.0000281 AC: 31 AN: 1101610

Other (OTH) AF: 0.00 AC: 0 AN: 59542

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74516

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.2
DANN	Benign	0.72
PhyloP100		-0.18
PromoterAI		-0.069	Neutral

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: rs562643282; hg19: chr3-42727116;