chr19-46755835-G-GTACC

Variant names:

• chr19-46755835-G-GTACC
• rs587777823
• NM_024301.5:c.387_390dupACCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024301.5(FKRP):​c.387_390dupACCT​(p.Asp131ThrfsTer2) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FKRP NM_024301.5 frameshift, stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.22
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 185 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-46755835-G-GTACC is Pathogenic according to our data. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-46755835-G-GTACC is described in CliVar as Pathogenic. Clinvar id is 4222.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.387_390dupACCT	p.Asp131ThrfsTer2	frameshift_variant, stop_gained	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.387_390dupACCT	p.Asp131ThrfsTer2	frameshift_variant, stop_gained	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:1

Dec 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587777823; hg19: chr19-47259092;