rs123509

Variant names:

• chr3-42691976-T-C
• rs123509
• NM_152393.4:c.1849T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152393.4(KLHL40):​c.1849T>C​(p.Cys617Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,604,172 control chromosomes in the GnomAD database, including 488,773 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C617H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.81 (50950 hom., cov: 32)
  • Exomes 𝑓: 0.77 (437823 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.26
• Publications: 48 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5673183E-7).
• BP6: Variant 3-42691976-T-C is Benign according to our data. Variant chr3-42691976-T-C is described in ClinVar as Benign. ClinVar VariationId is 226689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.1849T>C	p.Cys617Arg	missense	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.1849T>C	p.Cys617Arg	missense	Exon 6 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1834T>C	p.Cys612Arg	missense	Exon 6 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1828T>C	p.Cys610Arg	missense	Exon 6 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123746 AN: 152008 Hom.: 50889 Cov.: 32

Gnomad AFR AF: 0.915

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.807

GnomAD2 exomes AF: 0.815 AC: 204835 AN: 251286 AF XY: 0.811

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.738

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.758

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.774 AC: 1123927 AN: 1452044 Hom.: 437823 Cov.: 31 AF XY: 0.775 AC XY: 560375 AN XY: 723048

African (AFR) AF: 0.916 AC: 30494 AN: 33304

American (AMR) AF: 0.899 AC: 40187 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 19306 AN: 26080

East Asian (EAS) AF: 0.999 AC: 39616 AN: 39644

South Asian (SAS) AF: 0.856 AC: 73684 AN: 86062

European-Finnish (FIN) AF: 0.724 AC: 38652 AN: 53404

Middle Eastern (MID) AF: 0.846 AC: 4858 AN: 5742

European-Non Finnish (NFE) AF: 0.752 AC: 830009 AN: 1103084

Other (OTH) AF: 0.785 AC: 47121 AN: 60014

GnomAD4 genome AF: 0.814 AC: 123867 AN: 152128 Hom.: 50950 Cov.: 32 AF XY: 0.815 AC XY: 60629 AN XY: 74368

African (AFR) AF: 0.915 AC: 37990 AN: 41516

American (AMR) AF: 0.847 AC: 12960 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2556 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5144 AN: 5158

South Asian (SAS) AF: 0.870 AC: 4196 AN: 4822

European-Finnish (FIN) AF: 0.707 AC: 7491 AN: 10594

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50988 AN: 67956

Other (OTH) AF: 0.804 AC: 1695 AN: 2108

Alfa AF: 0.781 Hom.: 183395

Bravo AF: 0.830

TwinsUK AF: 0.753 AC: 2792

ALSPAC AF: 0.751 AC: 2895

ESP6500AA AF: 0.904 AC: 3985

ESP6500EA AF: 0.754 AC: 6487

ExAC AF: 0.817 AC: 99138

Asia WGS AF: 0.913 AC: 3176 AN: 3478

EpiCase AF: 0.759

EpiControl AF: 0.770

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Nemaline myopathy 8 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.44
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.092	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.0	N
PhyloP100		1.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	3.9	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.12
ClinPred		0.00035	T
GERP RS		3.3
Varity_R		0.25
gMVP		0.73
Mutation Taster		=97/3	polymorphism (auto)

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: rs123509; hg19: chr3-42733468; COSMIC: COSV107288969; COSMIC: COSV107288969;