NM_024301.5:c.427C>A

Variant names:

• chr19-46755877-C-A
• rs148206382
• NM_024301.5:c.427C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024301.5(FKRP):​c.427C>A​(p.Arg143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,493,634 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (30 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.56
• Publications: 12 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• 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 -19 ACMG points.

• 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 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability, myopathy caused by variation in FKRP, congenital muscular dystrophy with intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009333223).
• BP6: Variant 19-46755877-C-A is Benign according to our data. Variant chr19-46755877-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00362 (551/152318) while in subpopulation NFE AF = 0.00609 (414/68012). AF 95% confidence interval is 0.0056. There are 1 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 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.427C>A	p.Arg143Ser	missense	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.427C>A	p.Arg143Ser	missense	Exon 4 of 4	NP_001034974.1	Q9H9S5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.427C>A	p.Arg143Ser	missense	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000391909.7	TSL:2	c.427C>A	p.Arg143Ser	missense	Exon 4 of 4	ENSP00000375776.2	Q9H9S5
	FKRP	ENST00000908841.1		c.427C>A	p.Arg143Ser	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00448 AC: 445 AN: 99432 AF XY: 0.00418

Gnomad AFR exome AF: 0.000893

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.00342

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00730

GnomAD4 exome AF: 0.00542 AC: 7272 AN: 1341316 Hom.: 30 Cov.: 32 AF XY: 0.00540 AC XY: 3552 AN XY: 657222

African (AFR) AF: 0.000995 AC: 30 AN: 30144

American (AMR) AF: 0.00535 AC: 160 AN: 29892

Ashkenazi Jewish (ASJ) AF: 0.00278 AC: 62 AN: 22330

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 35016

South Asian (SAS) AF: 0.00478 AC: 350 AN: 73148

European-Finnish (FIN) AF: 0.000336 AC: 11 AN: 32716

Middle Eastern (MID) AF: 0.00736 AC: 39 AN: 5300

European-Non Finnish (NFE) AF: 0.00597 AC: 6311 AN: 1056860

Other (OTH) AF: 0.00551 AC: 308 AN: 55910

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74486

African (AFR) AF: 0.00101 AC: 42 AN: 41572

American (AMR) AF: 0.00353 AC: 54 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00434 AC: 21 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00467 Hom.: 0

Bravo AF: 0.00405

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00491 AC: 37

ExAC AF: 0.00190 AC: 177

Asia WGS AF: 0.000868 AC: 3 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2I (3)
-	-	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;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)
-	-	1	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0093	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.69
Sift	Benign	0.58	T
Sift4G	Benign	0.085	T
Polyphen		0.18	B
Vest4		0.58
MVP		0.98
MPC		0.83
ClinPred		0.0045	T
GERP RS		3.6
Varity_R		0.59
gMVP		0.79
Mutation Taster		=55/45	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: rs148206382; hg19: chr19-47259134; COSMIC: COSV105190863; COSMIC: COSV105190863;