rs28730867

Positions:

• chr2-169509786-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006063.3(KLHL41):​c.8C>T​(p.Ser3Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,609,052 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (196 hom.)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.57

Genes affected

KLHL41 (HGNC:16905): (kelch like family member 41) This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006108731).
• BP6: Variant 2-169509786-C-T is Benign according to our data. Variant chr2-169509786-C-T is described in ClinVar as [Benign]. Clinvar id is 259913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169509786-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00958 (1459/152296) while in subpopulation NFE AF= 0.0156 (1064/68022). AF 95% confidence interval is 0.0149. There are 10 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL41	NM_006063.3	c.8C>T	p.Ser3Phe	missense_variant	1/6	ENST00000284669.2	NP_006054.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2	c.8C>T	p.Ser3Phe	missense_variant	1/6	1	NM_006063.3	ENSP00000284669	P1

Frequencies

GnomAD3 genomes AF: 0.00957 AC: 1457 AN: 152178 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00960 AC: 2370 AN: 246946 Hom.: 26 AF XY: 0.0101 AC XY: 1345 AN XY: 133764

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00555

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00704

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.00989

GnomAD4 exome AF: 0.0143 AC: 20869 AN: 1456756 Hom.: 196 Cov.: 32 AF XY: 0.0142 AC XY: 10319 AN XY: 724688

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00639

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00707

Gnomad4 FIN exome AF: 0.00829

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00958 AC: 1459 AN: 152296 Hom.: 10 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74480

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00914

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0145 Hom.: 26

Bravo AF: 0.00885

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.0100 AC: 1217

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0157

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nemaline myopathy 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.17
Sift	Benign	0.036	D
Sift4G	Benign	0.067	T
Polyphen		0.94	P
Vest4		0.42
MPC		0.62
ClinPred		0.013	T
GERP RS		5.0
Varity_R		0.17
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28730867; hg19: chr2-170366296; COSMIC: COSV52930929; COSMIC: COSV52930929;