rs77138370

Variant names:

• chr19-46756272-C-G
• rs77138370
• NM_024301.5:c.822C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-46756272-C-G
• chr19-46756272-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_024301.5(FKRP):​c.822C>G​(p.Ile274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,508,888 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I274T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (5 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 1.13
• Publications: 3 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]

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: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_024301.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006845355).
• BP6: Variant 19-46756272-C-G is Benign according to our data. Variant chr19-46756272-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129058.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00308 (467/151746) while in subpopulation AFR AF = 0.0103 (426/41508). AF 95% confidence interval is 0.00946. There are 3 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	NM_024301.5	MANE Select	c.822C>G	p.Ile274Met	missense	Exon 4 of 4	NP_077277.1
	FKRP	NM_001039885.3		c.822C>G	p.Ile274Met	missense	Exon 4 of 4	NP_001034974.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.822C>G	p.Ile274Met	missense	Exon 4 of 4	ENSP00000326570.4
	FKRP	ENST00000391909.7	TSL:2	c.822C>G	p.Ile274Met	missense	Exon 4 of 4	ENSP00000375776.2
	FKRP	ENST00000908841.1		c.822C>G	p.Ile274Met	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 466 AN: 151638 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000687 AC: 79 AN: 114982 AF XY: 0.000493

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.000943

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000466

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000315 AC: 427 AN: 1357142 Hom.: 5 Cov.: 32 AF XY: 0.000250 AC XY: 167 AN XY: 667508

African (AFR) AF: 0.0109 AC: 333 AN: 30640

American (AMR) AF: 0.000586 AC: 19 AN: 32408

Ashkenazi Jewish (ASJ) AF: 0.000904 AC: 21 AN: 23226

East Asian (EAS) AF: 0.00 AC: 0 AN: 35070

South Asian (SAS) AF: 0.0000265 AC: 2 AN: 75484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34806

Middle Eastern (MID) AF: 0.000855 AC: 4 AN: 4678

European-Non Finnish (NFE) AF: 0.00000752 AC: 8 AN: 1064444

Other (OTH) AF: 0.000709 AC: 40 AN: 56386

GnomAD4 genome AF: 0.00308 AC: 467 AN: 151746 Hom.: 3 Cov.: 33 AF XY: 0.00263 AC XY: 195 AN XY: 74142

African (AFR) AF: 0.0103 AC: 426 AN: 41508

American (AMR) AF: 0.00184 AC: 28 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 3 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67724

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000685 Hom.: 0

Bravo AF: 0.00346

ESP6500AA AF: 0.00149 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000418 AC: 40

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.59
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	-0.29	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.043	D
Sift4G	Benign	0.061	T
Polyphen		0.0080	B
Vest4		0.28
MVP		0.83
MPC		0.65
ClinPred		0.0077	T
GERP RS		1.8
Varity_R		0.55
gMVP		0.86
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs77138370; hg19: chr19-47259529;