rs75079578

Variant names:

• chr19-46756035-C-T
• rs75079578
• NM_024301.5:c.585C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024301.5(FKRP):​c.585C>T​(p.Asp195Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,579,756 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (20 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.01
• Publications: 2 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: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-46756035-C-T is Benign according to our data. Variant chr19-46756035-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00997 (1516/152028) while in subpopulation AFR AF = 0.0325 (1350/41492). AF 95% confidence interval is 0.0311. There are 19 homozygotes in GnomAd4. There are 686 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	NM_024301.5	MANE Select	c.585C>T	p.Asp195Asp	synonymous	Exon 4 of 4	NP_077277.1
	FKRP	NM_001039885.3		c.585C>T	p.Asp195Asp	synonymous	Exon 4 of 4	NP_001034974.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.585C>T	p.Asp195Asp	synonymous	Exon 4 of 4	ENSP00000326570.4
	FKRP	ENST00000391909.7	TSL:2	c.585C>T	p.Asp195Asp	synonymous	Exon 4 of 4	ENSP00000375776.2
	FKRP	ENST00000597339.5	TSL:5	n.247-5798C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1511 AN: 151918 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00204 AC: 398 AN: 194854 AF XY: 0.00158

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.000906

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000987 AC: 1409 AN: 1427728 Hom.: 20 Cov.: 32 AF XY: 0.000816 AC XY: 579 AN XY: 709610

African (AFR) AF: 0.0332 AC: 1065 AN: 32112

American (AMR) AF: 0.00206 AC: 88 AN: 42708

Ashkenazi Jewish (ASJ) AF: 0.000902 AC: 23 AN: 25494

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38330

South Asian (SAS) AF: 0.0000360 AC: 3 AN: 83448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36964

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5722

European-Non Finnish (NFE) AF: 0.0000716 AC: 79 AN: 1103596

Other (OTH) AF: 0.00239 AC: 142 AN: 59354

GnomAD4 genome AF: 0.00997 AC: 1516 AN: 152028 Hom.: 19 Cov.: 33 AF XY: 0.00923 AC XY: 686 AN XY: 74336

African (AFR) AF: 0.0325 AC: 1350 AN: 41492

American (AMR) AF: 0.00818 AC: 125 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67928

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00380 Hom.: 1

Bravo AF: 0.0115

Asia WGS AF: 0.00290 AC: 10 AN: 3458

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	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	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.8
DANN	Benign	0.74
PhyloP100		-3.0
Mutation Taster		=100/0	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: rs75079578; hg19: chr19-47259292;