chr19-46746070-T-TGGCGGC

Variant names:

• chr19-46746070-T-TGGCGGC
• rs995093352
• NM_024301.5:c.-263_-258dupGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024301.5(FKRP):​c.-263_-258dupGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000469 in 1,216,562 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 0.00013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: FKRP NM_024301.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.763
• 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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.-263_-258dupGGCGGC		5_prime_UTR_variant	Exon 1 of 4	ENST00000318584.10	NP_077277.1
STRN4	NM_013403.3	c.282+73_282+78dupGCCGCC		intron_variant	Intron 1 of 17	ENST00000263280.11	NP_037535.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.-263_-258dupGGCGGC		5_prime_UTR_variant	Exon 1 of 4	1	NM_024301.5	ENSP00000326570.4
STRN4	ENST00000263280.11	c.282+73_282+78dupGCCGCC		intron_variant	Intron 1 of 17	1	NM_013403.3	ENSP00000263280.4

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 18 AN: 150254 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000489

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: 0.000577

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 38 AN: 1066200 Hom.: 0 Cov.: 26 AF XY: 0.0000386 AC XY: 20 AN XY: 518546

African (AFR) AF: 0.0000521 AC: 1 AN: 19190

American (AMR) AF: 0.00 AC: 0 AN: 6438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11758

East Asian (EAS) AF: 0.000237 AC: 5 AN: 21106

South Asian (SAS) AF: 0.0000449 AC: 2 AN: 44558

European-Finnish (FIN) AF: 0.000514 AC: 11 AN: 21406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2896

European-Non Finnish (NFE) AF: 0.0000189 AC: 17 AN: 897864

Other (OTH) AF: 0.0000488 AC: 2 AN: 40984

GnomAD4 genome AF: 0.000126 AC: 19 AN: 150362 Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 8 AN XY: 73440

African (AFR) AF: 0.0000731 AC: 3 AN: 41042

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4952

South Asian (SAS) AF: 0.00 AC: 0 AN: 4680

European-Finnish (FIN) AF: 0.000577 AC: 6 AN: 10392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67348

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76

Splicing

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

Other links and lift over

dbSNP: rs995093352; hg19: chr19-47249327;