2-169509975-T-C

Position:

• chr2-169509975-T-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/exons	MANE	Protein	UniProt
KLHL41	NM_006063.3	c.197T>C	p.Ile66Thr	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.197T>C	p.Ile66Thr	missense_variant	1/6	1	NM_006063.3	ENSP00000284669.1
ENSG00000251569	ENST00000513963.1	c.925-4599T>C		intron_variant		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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2021

- -

Nemaline myopathy 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

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;