chr19-46746094-AGGCCG-A

Variant names:

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

Variant summary

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

The NM_013403.3(STRN4):​c.282+50_282+54delCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,244,078 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: STRN4 NM_013403.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73
• 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 361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN4	NM_013403.3	c.282+50_282+54delCGGCC		intron_variant	Intron 1 of 17	ENST00000263280.11	NP_037535.2
FKRP	NM_024301.5	c.-253+22_-253+26delCCGGG		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+50_282+54delCGGCC		intron_variant	Intron 1 of 17	1	NM_013403.3	ENSP00000263280.4
FKRP	ENST00000318584.10	c.-253+5_-253+9delGGCCG		splice_region_variant, intron_variant	Intron 1 of 3	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 359 AN: 145682 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000647

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00200

GnomAD4 exome AF: 0.000316 AC: 347 AN: 1098290 Hom.: 1 AF XY: 0.000283 AC XY: 152 AN XY: 536622

African (AFR) AF: 0.00980 AC: 194 AN: 19794

American (AMR) AF: 0.000755 AC: 7 AN: 9270

Ashkenazi Jewish (ASJ) AF: 0.0000775 AC: 1 AN: 12898

East Asian (EAS) AF: 0.000182 AC: 3 AN: 16456

South Asian (SAS) AF: 0.000284 AC: 16 AN: 56418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19632

Middle Eastern (MID) AF: 0.000292 AC: 1 AN: 3420

European-Non Finnish (NFE) AF: 0.000112 AC: 103 AN: 919458

Other (OTH) AF: 0.000537 AC: 22 AN: 40944

GnomAD4 genome AF: 0.00248 AC: 361 AN: 145788 Hom.: 0 Cov.: 28 AF XY: 0.00221 AC XY: 157 AN XY: 71050

African (AFR) AF: 0.00833 AC: 329 AN: 39484

American (AMR) AF: 0.00101 AC: 15 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: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.000151 AC: 10 AN: 66172

Other (OTH) AF: 0.00198 AC: 4 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		1.7

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;