19-46756207-G-A

Position:

• chr19-46756207-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024301.5(FKRP):​c.757G>A​(p.Ala253Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000772 in 1,294,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34504247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.757G>A	p.Ala253Thr	missense_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.757G>A	p.Ala253Thr	missense_variant	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7	c.757G>A	p.Ala253Thr	missense_variant	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5	n.247-5626G>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7542G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1294852 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 636326

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.0061
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.66	.;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.77	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.45	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.61	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.68	P;P
Vest4		0.12
MutPred		0.24		Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);
MVP		0.90
MPC		0.73
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.80

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: rs959679901; hg19: chr19-47259464;