rs200990647

Variant names:

• chr19-46755970-A-T
• rs200990647
• NM_024301.5:c.520A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-46755970-A-T
• chr19-46755970-A-C
• chr19-46755970-A-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024301.5(FKRP):​c.520A>T​(p.Ser174Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,539,596 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S174S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (26 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.74
• Publications: 5 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_024301.5
• 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 autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009832382).
• BP6: Variant 19-46755970-A-T is Benign according to our data. Variant chr19-46755970-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00154 (234/152222) while in subpopulation SAS AF = 0.019 (92/4830). AF 95% confidence interval is 0.0159. There are 3 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.520A>T	p.Ser174Cys	missense	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.520A>T	p.Ser174Cys	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.520A>T	p.Ser174Cys	missense	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000391909.7	TSL:2	c.520A>T	p.Ser174Cys	missense	Exon 4 of 4	ENSP00000375776.2	Q9H9S5
	FKRP	ENST00000908841.1		c.520A>T	p.Ser174Cys	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152110 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0194

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00356 AC: 482 AN: 135390 AF XY: 0.00449

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00332

Gnomad FIN exome AF: 0.000160

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00232 AC: 3215 AN: 1387374 Hom.: 26 Cov.: 32 AF XY: 0.00267 AC XY: 1831 AN XY: 685494

African (AFR) AF: 0.000159 AC: 5 AN: 31432

American (AMR) AF: 0.000639 AC: 23 AN: 35978

Ashkenazi Jewish (ASJ) AF: 0.000997 AC: 25 AN: 25072

East Asian (EAS) AF: 0.00108 AC: 39 AN: 35980

South Asian (SAS) AF: 0.0144 AC: 1147 AN: 79400

European-Finnish (FIN) AF: 0.000203 AC: 7 AN: 34442

Middle Eastern (MID) AF: 0.000703 AC: 4 AN: 5686

European-Non Finnish (NFE) AF: 0.00168 AC: 1813 AN: 1081420

Other (OTH) AF: 0.00262 AC: 152 AN: 57964

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152222 Hom.: 3 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74418

African (AFR) AF: 0.000409 AC: 17 AN: 41550

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5174

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000575 Hom.: 0

Bravo AF: 0.00111

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000926 AC: 7

ExAC AF: 0.00239 AC: 257

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2I (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)
-	-	1	not provided (1)
-	-	1	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0	B
Vest4		0.49
MVP		0.84
MPC		1.3
ClinPred		0.028	T
GERP RS		3.5
Varity_R		0.49
gMVP		0.71
Mutation Taster		=47/53	disease causing

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: rs200990647; hg19: chr19-47259227; COSMIC: COSV100586739; COSMIC: COSV100586739;