rs368981218

chr9-105575054-G-Achr9-105575054-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001079802.2(FKTN):c.22G>A(p.Val8Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000293 in 1,604,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.64

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a transmembrane_region Helical; Signal-anchor for type II membrane protein (size 20) in uniprot entity FKTN_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001079802.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKTN	NM_001079802.2	c.22G>A	p.Val8Met	missense_variant	3/11	ENST00000357998.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKTN	ENST00000357998.10	c.22G>A	p.Val8Met	missense_variant	3/11	5	NM_001079802.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251326 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000275 AC: 40 AN: 1452180 Hom.: 0 Cov.: 28 AF XY: 0.0000359 AC XY: 26 AN XY: 723228

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000308

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Walker-Warburg congenital muscular dystrophy Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 19, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 8 of the FKTN protein (p.Val8Met). This variant is present in population databases (rs368981218, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 566394). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.079	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.69
MutPred		0.25		Loss of ubiquitination at K6 (P = 0.0736);Loss of ubiquitination at K6 (P = 0.0736);Loss of ubiquitination at K6 (P = 0.0736);Loss of ubiquitination at K6 (P = 0.0736);
MVP		0.90
MPC		0.46
ClinPred		0.42	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368981218; hg19: chr9-108337335;