chr19-46756047-G-A

Variant names:

• chr19-46756047-G-A
• rs1360004383
• NM_024301.5:c.597G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_024301.5(FKRP):​c.597G>A​(p.Val199Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. V199V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.710
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-46756047-G-A is Benign according to our data. Variant chr19-46756047-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2909251.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.71 with no splicing effect.

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.597G>A	p.Val199Val	synonymous	Exon 4 of 4	NP_077277.1
	FKRP	NM_001039885.3		c.597G>A	p.Val199Val	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.597G>A	p.Val199Val	synonymous	Exon 4 of 4	ENSP00000326570.4
	FKRP	ENST00000391909.7	TSL:2	c.597G>A	p.Val199Val	synonymous	Exon 4 of 4	ENSP00000375776.2
	FKRP	ENST00000597339.5	TSL:5	n.247-5786G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151856 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 708734

African (AFR) AF: 0.00 AC: 0 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 42748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25392

East Asian (EAS) AF: 0.00 AC: 0 AN: 38096

South Asian (SAS) AF: 0.00 AC: 0 AN: 83334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103024

Other (OTH) AF: 0.00 AC: 0 AN: 59284

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151856 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74178

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Benign:1

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.6
DANN	Benign	0.52
PhyloP100		0.71

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: rs1360004383; hg19: chr19-47259304;