rs28937902

chr19-46756113-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_024301.5(FKRP):c.663C>A(p.Ser221Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0240

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 19-46756113-C-A is Pathogenic according to our data. Variant chr19-46756113-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4225.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-46756113-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.663C>A	p.Ser221Arg	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.663C>A	p.Ser221Arg	missense_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7	c.663C>A	p.Ser221Arg	missense_variant	4/4	2		P1
FKRP	ENST00000597339.5	n.247-5720C>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7448C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1373026 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 679206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy type B5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 25, 2003

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.96	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.98	D;D
Vest4		0.61
MutPred		0.81		Gain of MoRF binding (P = 0.0185);Gain of MoRF binding (P = 0.0185);
MVP		0.99
MPC		1.2
ClinPred		0.87	D
GERP RS		3.1
Varity_R		0.73
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28937902; hg19: chr19-47259370;