2-169510589-G-T

Variant names:

• chr2-169510589-G-T
• rs28763868
• NM_006063.3:c.811G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006063.3(KLHL41):​c.811G>T​(p.Ala271Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A271T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 18 publications found

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]

KLHL41 Gene-Disease associations (from GenCC):

• nemaline myopathy 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251569 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06412712).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006063.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL41	NM_006063.3	MANE Select	c.811G>T	p.Ala271Ser	missense	Exon 1 of 6	NP_006054.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL41	ENST00000284669.2	TSL:1 MANE Select	c.811G>T	p.Ala271Ser	missense	Exon 1 of 6	ENSP00000284669.1
	ENSG00000251569	ENST00000513963.1	TSL:2	c.925-3985G>T		intron	N/A	ENSP00000424363.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 3387

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.0
DANN	Benign	0.63
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	N
PhyloP100		3.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.076
Sift	Benign	0.72	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.091
MutPred		0.30		Gain of glycosylation at A271 (P = 0.0553)
MVP		0.23
MPC		0.28
ClinPred		0.044	T
GERP RS		2.6
Varity_R		0.036
gMVP		0.32
Mutation Taster		=98/2	polymorphism

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: rs28763868; hg19: chr2-170367099;