rs959679901

Variant names:

• chr19-46756207-G-T
• rs959679901
• NM_024301.5:c.757G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-46756207-G-T
• chr19-46756207-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_024301.5(FKRP):​c.757G>T​(p.Ala253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A253A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• myopathy caused by variation in FKRP

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability, myopathy caused by variation in FKRP, congenital muscular dystrophy with intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31375167).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024301.5. 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
	FKRP	NM_024301.5	MANE Select	c.757G>T	p.Ala253Ser	missense	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.757G>T	p.Ala253Ser	missense	Exon 4 of 4	NP_001034974.1	Q9H9S5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.757G>T	p.Ala253Ser	missense	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000391909.7	TSL:2	c.757G>T	p.Ala253Ser	missense	Exon 4 of 4	ENSP00000375776.2	Q9H9S5
	FKRP	ENST00000908841.1		c.757G>T	p.Ala253Ser	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 151122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1294852 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 636326

African (AFR) AF: 0.0000401 AC: 1 AN: 24920

American (AMR) AF: 0.00 AC: 0 AN: 21060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20796

East Asian (EAS) AF: 0.00 AC: 0 AN: 28922

South Asian (SAS) AF: 0.00 AC: 0 AN: 69496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5022

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038792

Other (OTH) AF: 0.00 AC: 0 AN: 53264

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 151122 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73790

African (AFR) AF: 0.0000242 AC: 1 AN: 41310

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67722

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2I (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.0040	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.90	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.44
Sift	Benign	0.84	T
Sift4G	Benign	0.75	T
Polyphen		0.49	P
Vest4		0.097
MutPred		0.26		Gain of loop (P = 0.0195)
MVP		0.87
MPC		0.72
ClinPred		0.14	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.76
Mutation Taster		=90/10	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: rs959679901; hg19: chr19-47259464;