19-46746094-A-AGGCCG

Variant names:

• chr19-46746094-A-AGGCCG
• rs568014119
• NM_013403.3:c.282+50_282+54dupCGGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000318584.10(FKRP):​c.-253+4_-253+5insGGCCG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,242,240 control chromosomes in the GnomAD database, including 8,217 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (714 hom., cov: 28)
  • Exomes 𝑓: 0.12 (7503 hom.)
• Consequence: FKRP ENST00000318584.10 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770
• Publications: 2 publications found

Genes affected

STRN4 (HGNC:15721): (striatin 4) Enables armadillo repeat domain binding activity and protein phosphatase 2A binding activity. Part of FAR/SIN/STRIPAK complex. [provided by Alliance of Genome Resources, Apr 2022]

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 -10 ACMG points.

• BP6: Variant 19-46746094-A-AGGCCG is Benign according to our data. Variant chr19-46746094-A-AGGCCG is described in ClinVar as [Benign]. Clinvar id is 516899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN4	NM_013403.3	c.282+50_282+54dupCGGCC		intron_variant	Intron 1 of 17	ENST00000263280.11	NP_037535.2
FKRP	NM_024301.5	c.-253+22_-253+26dupCCGGG		intron_variant	Intron 1 of 3	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRN4	ENST00000263280.11	c.282+54_282+55insCGGCC		intron_variant	Intron 1 of 17	1	NM_013403.3	ENSP00000263280.4
FKRP	ENST00000318584.10	c.-253+4_-253+5insGGCCG		splice_region_variant, intron_variant	Intron 1 of 3	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 12920 AN: 145596 Hom.: 715 Cov.: 28

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.0441

Gnomad AMR AF: 0.0690

Gnomad ASJ AF: 0.0826

Gnomad EAS AF: 0.00841

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0791

GnomAD4 exome AF: 0.120 AC: 131185 AN: 1096538 Hom.: 7503 Cov.: 34 AF XY: 0.118 AC XY: 63325 AN XY: 535702

African (AFR) AF: 0.0500 AC: 990 AN: 19786

American (AMR) AF: 0.0650 AC: 602 AN: 9264

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 1256 AN: 12882

East Asian (EAS) AF: 0.00553 AC: 91 AN: 16462

South Asian (SAS) AF: 0.0466 AC: 2618 AN: 56146

European-Finnish (FIN) AF: 0.141 AC: 2759 AN: 19504

Middle Eastern (MID) AF: 0.0929 AC: 317 AN: 3414

European-Non Finnish (NFE) AF: 0.129 AC: 118130 AN: 918208

Other (OTH) AF: 0.108 AC: 4422 AN: 40872

GnomAD4 genome AF: 0.0887 AC: 12922 AN: 145702 Hom.: 714 Cov.: 28 AF XY: 0.0849 AC XY: 6030 AN XY: 71016

African (AFR) AF: 0.0506 AC: 1998 AN: 39470

American (AMR) AF: 0.0689 AC: 1018 AN: 14774

Ashkenazi Jewish (ASJ) AF: 0.0826 AC: 280 AN: 3390

East Asian (EAS) AF: 0.00844 AC: 39 AN: 4622

South Asian (SAS) AF: 0.0517 AC: 226 AN: 4370

European-Finnish (FIN) AF: 0.105 AC: 1026 AN: 9806

Middle Eastern (MID) AF: 0.112 AC: 29 AN: 260

European-Non Finnish (NFE) AF: 0.123 AC: 8111 AN: 66132

Other (OTH) AF: 0.0779 AC: 157 AN: 2016

Alfa AF: 0.0332 Hom.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.077
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs568014119; hg19: chr19-47249351;