9-105618074-C-A

Position:

• chr9-105618074-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001079802.2(FKTN):​c.1026C>A​(p.Leu342=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,606,314 control chromosomes in the GnomAD database, including 70,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5818 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64747 hom.)
• Consequence: FKTN NM_001079802.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.635

Genes affected

FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 9-105618074-C-A is Benign according to our data. Variant chr9-105618074-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 93510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105618074-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.635 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKTN	NM_001079802.2	c.1026C>A	p.Leu342=	synonymous_variant	9/11	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10	c.1026C>A	p.Leu342=	synonymous_variant	9/11	5	NM_001079802.2	ENSP00000350687	P1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41066 AN: 151948 Hom.: 5809 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.0947

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.253 AC: 63477 AN: 250748 Hom.: 8922 AF XY: 0.247 AC XY: 33453 AN XY: 135676

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.0915

Gnomad SAS exome AF: 0.0967

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.290 AC: 421143 AN: 1454250 Hom.: 64747 Cov.: 30 AF XY: 0.284 AC XY: 205289 AN XY: 723890

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.0982

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.270 AC: 41114 AN: 152064 Hom.: 5818 Cov.: 32 AF XY: 0.265 AC XY: 19708 AN XY: 74346

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.0954

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.277

Alfa AF: 0.295 Hom.: 13576

Bravo AF: 0.269

Asia WGS AF: 0.126 AC: 438 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.299

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Leu342Leu in exon 9 of FKTN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 31.8% (2731/8596) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17309806). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dilated cardiomyopathy 1X Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Walker-Warburg congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.0
DANN	Benign	0.65

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: rs17309806; hg19: chr9-108380355; COSMIC: COSV56311244; COSMIC: COSV56311244;