rs34006675

Variant names:

• chr9-105604218-G-A
• rs34006675
• NM_001079802.2:c.373G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001079802.2(FKTN):​c.373G>A​(p.Gly125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,204 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G125A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (165 hom., cov: 32)
  • Exomes 𝑓: 0.012 (224 hom.)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: 1.68
• Publications: 9 publications found

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]

FKTN Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2M

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in FKTN

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1X

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-105604218-G-A is Benign according to our data. Variant chr9-105604218-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0855 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079802.2. 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
	FKTN	NM_001079802.2	MANE Select	c.373G>A	p.Gly125Ser	missense	Exon 6 of 11	NP_001073270.1	O75072-1
	FKTN	NM_001351496.2		c.373G>A	p.Gly125Ser	missense	Exon 7 of 12	NP_001338425.1	O75072-1
	FKTN	NM_006731.2		c.373G>A	p.Gly125Ser	missense	Exon 5 of 10	NP_006722.2	O75072-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKTN	ENST00000357998.10	TSL:5 MANE Select	c.373G>A	p.Gly125Ser	missense	Exon 6 of 11	ENSP00000350687.6	O75072-1
	FKTN	ENST00000223528.6	TSL:1	c.373G>A	p.Gly125Ser	missense	Exon 5 of 10	ENSP00000223528.2	O75072-1
	FKTN	ENST00000602526.1	TSL:1	n.*411G>A		non_coding_transcript_exon	Exon 6 of 11	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4789 AN: 152122 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0138 AC: 3450 AN: 249614 AF XY: 0.0122

Gnomad AFR exome AF: 0.0905

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0117 AC: 17068 AN: 1459964 Hom.: 224 Cov.: 32 AF XY: 0.0111 AC XY: 8073 AN XY: 726308

African (AFR) AF: 0.0917 AC: 3064 AN: 33412

American (AMR) AF: 0.0108 AC: 485 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 160 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00315 AC: 271 AN: 86168

European-Finnish (FIN) AF: 0.00696 AC: 372 AN: 53410

Middle Eastern (MID) AF: 0.0293 AC: 126 AN: 4294

European-Non Finnish (NFE) AF: 0.0105 AC: 11715 AN: 1111906

Other (OTH) AF: 0.0145 AC: 874 AN: 60222

GnomAD4 genome AF: 0.0315 AC: 4795 AN: 152240 Hom.: 165 Cov.: 32 AF XY: 0.0299 AC XY: 2222 AN XY: 74434

African (AFR) AF: 0.0879 AC: 3649 AN: 41510

American (AMR) AF: 0.0144 AC: 220 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4820

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 753 AN: 68020

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0177 Hom.: 223

Bravo AF: 0.0348

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.0867 AC: 382

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.0153 AC: 1862

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	1	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (2)
-	-	2	Walker-Warburg congenital muscular dystrophy (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.24
Sift	Benign	0.36	T
Sift4G	Benign	0.65	T
Polyphen		0.047	B
Vest4		0.23
MPC		0.082
ClinPred		0.019	T
GERP RS		1.7
Varity_R		0.057
gMVP		0.61
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34006675; hg19: chr9-108366499; COSMIC: COSV107302123;