19-46746094-AGGCCGGGCCG-AGGCCGGGCCGGGCCGGGCCG

Variant names:

• chr19-46746094-A-AGGCCGGGCCG
• rs568014119
• NM_013403.3:c.282+45_282+54dupCGGCCCGGCC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_013403.3(STRN4):​c.282+45_282+54dupCGGCCCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000996 in 1,244,466 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: STRN4 NM_013403.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN4	NM_013403.3	c.282+45_282+54dupCGGCCCGGCC		intron_variant	Intron 1 of 17	ENST00000263280.11	NP_037535.2
FKRP	NM_024301.5	c.-253+17_-253+26dupCCGGGCCGGG		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+55insCGGCCCGGCC		intron_variant	Intron 1 of 17	1	NM_013403.3	ENSP00000263280.4
FKRP	ENST00000318584.10	c.-253+4_-253+5insGGCCGGGCCG		splice_region_variant, intron_variant	Intron 1 of 3	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 15 AN: 145684 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000647

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00365

Gnomad NFE AF: 0.000106

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 109 AN: 1098676 Hom.: 0 Cov.: 34 AF XY: 0.0000931 AC XY: 50 AN XY: 536838

African (AFR) AF: 0.00 AC: 0 AN: 19800

American (AMR) AF: 0.00 AC: 0 AN: 9284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12914

East Asian (EAS) AF: 0.0000607 AC: 1 AN: 16466

South Asian (SAS) AF: 0.0000354 AC: 2 AN: 56476

European-Finnish (FIN) AF: 0.000102 AC: 2 AN: 19658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3420

European-Non Finnish (NFE) AF: 0.000113 AC: 104 AN: 919694

Other (OTH) AF: 0.00 AC: 0 AN: 40964

GnomAD4 genome AF: 0.000103 AC: 15 AN: 145790 Hom.: 0 Cov.: 28 AF XY: 0.0000704 AC XY: 5 AN XY: 71052

African (AFR) AF: 0.000101 AC: 4 AN: 39486

American (AMR) AF: 0.00 AC: 0 AN: 14782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.000649 AC: 3 AN: 4622

South Asian (SAS) AF: 0.00 AC: 0 AN: 4370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9826

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.000106 AC: 7 AN: 66172

Other (OTH) AF: 0.00 AC: 0 AN: 2018

Alfa AF: 0.00 Hom.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.077

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;