rs9872183

Variant names:

• chr3-42688240-C-G
• rs9872183
• NM_152393.4:c.1251C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-42688240-C-G
• chr3-42688240-C-A
• chr3-42688240-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_152393.4(KLHL40):​c.1251C>G​(p.Val417Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,946 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (24 hom.)
• Consequence: KLHL40 NM_152393.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.48
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-42688240-C-G is Benign according to our data. Variant chr3-42688240-C-G is described in ClinVar as Benign. ClinVar VariationId is 380835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1601/152140) while in subpopulation AFR AF = 0.0369 (1530/41492). AF 95% confidence interval is 0.0353. There are 34 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.1251C>G	p.Val417Val	synonymous	Exon 2 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.1251C>G	p.Val417Val	synonymous	Exon 2 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1251C>G	p.Val417Val	synonymous	Exon 2 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1251C>G	p.Val417Val	synonymous	Exon 2 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1602 AN: 152022 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

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: 0.0000882

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00261 AC: 655 AN: 251308 AF XY: 0.00196

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00103 AC: 1512 AN: 1461806 Hom.: 24 Cov.: 32 AF XY: 0.000876 AC XY: 637 AN XY: 727200

African (AFR) AF: 0.0375 AC: 1257 AN: 33478

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1112006

Other (OTH) AF: 0.00227 AC: 137 AN: 60396

GnomAD4 genome AF: 0.0105 AC: 1601 AN: 152140 Hom.: 34 Cov.: 31 AF XY: 0.00999 AC XY: 743 AN XY: 74358

African (AFR) AF: 0.0369 AC: 1530 AN: 41492

American (AMR) AF: 0.00353 AC: 54 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.0128

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.5
DANN	Benign	0.75
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9872183; hg19: chr3-42729732;