2-169509975-T-C

Variant names:

• chr2-169509975-T-C
• rs116809051
• NM_006063.3:c.197T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_006063.3(KLHL41):​c.197T>C​(p.Ile66Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000484 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.49

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]

ENSG00000251569 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035518706).
• BP6: Variant 2-169509975-T-C is Benign according to our data. Variant chr2-169509975-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 474869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00134 (204/152250) while in subpopulation AFR AF= 0.00334 (139/41562). AF 95% confidence interval is 0.00289. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL41	NM_006063.3	c.197T>C	p.Ile66Thr	missense_variant	Exon 1 of 6	ENST00000284669.2	NP_006054.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2	c.197T>C	p.Ile66Thr	missense_variant	Exon 1 of 6	1	NM_006063.3	ENSP00000284669.1
ENSG00000251569	ENST00000513963.1	c.925-4599T>C		intron_variant	Intron 11 of 15	2		ENSP00000424363.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000855 AC: 215 AN: 251418 Hom.: 1 AF XY: 0.000736 AC XY: 100 AN XY: 135884

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00813

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000395 AC: 577 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.000378 AC XY: 275 AN XY: 727228

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74432

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000740 Hom.: 1

Bravo AF: 0.00155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KLHL41-related disorder Benign:1

Jun 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 9 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Benign	0.57	T
Sift4G	Benign	0.40	T
Polyphen		0.010	B
Vest4		0.30
MVP		0.80
MPC		0.38
ClinPred		0.021	T
GERP RS		5.2
Varity_R		0.097
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs116809051; hg19: chr2-170366485;