NM_006063.3:c.1569T>C

Variant names:

• chr2-169520867-T-C
• rs373954289
• NM_006063.3:c.1569T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006063.3(KLHL41):​c.1569T>C​(p.Asp523Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,609,872 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: KLHL41 NM_006063.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0560
• Publications: 0 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-169520867-T-C is Benign according to our data. Variant chr2-169520867-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 474865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.056 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000361 (55/152350) while in subpopulation AMR AF = 0.000719 (11/15308). AF 95% confidence interval is 0.000402. There are 1 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL41	NM_006063.3	MANE Select	c.1569T>C	p.Asp523Asp	synonymous	Exon 5 of 6	NP_006054.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL41	ENST00000284669.2	TSL:1 MANE Select	c.1569T>C	p.Asp523Asp	synonymous	Exon 5 of 6	ENSP00000284669.1	O60662-1
	ENSG00000251569	ENST00000513963.1	TSL:2	c.1383T>C	p.Asp461Asp	synonymous	Exon 15 of 16	ENSP00000424363.1	E9PBE3
	KLHL41	ENST00000946624.1		c.1602T>C	p.Asp534Asp	synonymous	Exon 5 of 6	ENSP00000616683.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.000279 AC: 70 AN: 250494 AF XY: 0.000340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000325 AC: 474 AN: 1457522 Hom.: 3 Cov.: 29 AF XY: 0.000358 AC XY: 260 AN XY: 725372

African (AFR) AF: 0.000360 AC: 12 AN: 33350

American (AMR) AF: 0.000494 AC: 22 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000349 AC: 30 AN: 85972

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.0160 AC: 92 AN: 5760

European-Non Finnish (NFE) AF: 0.000249 AC: 276 AN: 1108518

Other (OTH) AF: 0.000664 AC: 40 AN: 60222

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74502

African (AFR) AF: 0.000120 AC: 5 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000589 Hom.: 1

Bravo AF: 0.000525

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Nemaline myopathy 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.5
DANN	Benign	0.75
PhyloP100		0.056
Mutation Taster		=100/0	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: rs373954289; hg19: chr2-170377377; COSMIC: COSV52929394;