rs200613578

Variant names:

• chr3-42686266-G-A
• rs200613578
• NM_152393.4:c.648G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-42686266-G-A
• chr3-42686266-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_152393.4(KLHL40):​c.648G>A​(p.Ala216Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A216A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL40 NM_152393.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.861
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=-0.861 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL40	NM_152393.4	c.648G>A	p.Ala216Ala	synonymous_variant	Exon 1 of 6	ENST00000287777.5	NP_689606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5	c.648G>A	p.Ala216Ala	synonymous_variant	Exon 1 of 6	1	NM_152393.4	ENSP00000287777.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1404824 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2 AN XY: 693542

African (AFR) AF: 0.00 AC: 0 AN: 31992

American (AMR) AF: 0.00 AC: 0 AN: 36940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24612

East Asian (EAS) AF: 0.00 AC: 0 AN: 36784

South Asian (SAS) AF: 0.00 AC: 0 AN: 80808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5026

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083744

Other (OTH) AF: 0.00 AC: 0 AN: 57966

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.2
DANN	Benign	0.95
PhyloP100		-0.86

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: rs200613578; hg19: chr3-42727758;