rs28763868

Positions:

• chr2-169510589-G-A
• chr2-169510589-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000284669.2(KLHL41):​c.811G>A​(p.Ala271Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,940 control chromosomes in the GnomAD database, including 8,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A271V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.081 (639 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8213 hom.)
• Consequence: KLHL41 ENST00000284669.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.02

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=0.0016920269).
• BP6: Variant 2-169510589-G-A is Benign according to our data. Variant chr2-169510589-G-A is described in ClinVar as [Benign]. Clinvar id is 259911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL41	NM_006063.3	c.811G>A	p.Ala271Thr	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.811G>A	p.Ala271Thr	missense_variant	1/6	1	NM_006063.3	ENSP00000284669	P1

Frequencies

GnomAD3 genomes AF: 0.0810 AC: 12315 AN: 152026 Hom.: 640 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0831

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0770

GnomAD3 exomes AF: 0.0857 AC: 21553 AN: 251440 Hom.: 1078 AF XY: 0.0882 AC XY: 11981 AN XY: 135896

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.0485

Gnomad ASJ exome AF: 0.0712

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.0811

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0911

GnomAD4 exome AF: 0.102 AC: 149111 AN: 1461796 Hom.: 8213 Cov.: 33 AF XY: 0.101 AC XY: 73802 AN XY: 727202

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.0507

Gnomad4 ASJ exome AF: 0.0750

Gnomad4 EAS exome AF: 0.00786

Gnomad4 SAS exome AF: 0.0763

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.0910

GnomAD4 genome AF: 0.0809 AC: 12310 AN: 152144 Hom.: 639 Cov.: 32 AF XY: 0.0805 AC XY: 5985 AN XY: 74380

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.0663

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.0832

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.101 Hom.: 1748

Bravo AF: 0.0753

TwinsUK AF: 0.116 AC: 429

ALSPAC AF: 0.115 AC: 443

ESP6500AA AF: 0.0420 AC: 185

ESP6500EA AF: 0.112 AC: 959

ExAC AF: 0.0874 AC: 10613

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.99	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.15
Sift	Benign	0.51	T
Sift4G	Benign	0.55	T
Polyphen		0.0030	B
Vest4		0.044
MPC		0.29
ClinPred		0.0091	T
GERP RS		2.6
Varity_R		0.032
gMVP		0.35

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: rs28763868; hg19: chr2-170367099; COSMIC: COSV52929467; COSMIC: COSV52929467;