19-46746379-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013403.3(STRN4):c.52C>T(p.Arg18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000094 in 1,127,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000075 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

STRN4
NM_013403.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

Publications

1 publications found

Variant links:

Genes affected

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]

STRN4 links:

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

FKRP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16762576).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN4	NM_013403.3 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 1 of 18	ENST00000263280.11	NP_037535.2	Q9NRL3-1
FKRP	NM_024301.5 link	c.-253+289G>A		intron_variant	Intron 1 of 3	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRN4	ENST00000263280.11 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 1 of 18	1	NM_013403.3	ENSP00000263280.4		Q9NRL3-1
FKRP	ENST00000318584.10 link	c.-253+289G>A		intron_variant	Intron 1 of 3	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.0000748

AC:

AN:

147038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000671

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000136

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000969

AC:

AN:

980508

Hom.:

Cov.:

AF XY:

0.0000997

AC XY:

AN XY:

461526

show subpopulations

African (AFR)

AF:

0.0000514

AC:

AN:

19444

American (AMR)

AF:

0.00

AC:

AN:

5246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10074

East Asian (EAS)

AF:

0.0000602

AC:

AN:

16620

South Asian (SAS)

AF:

0.0000538

AC:

AN:

18594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2396

European-Non Finnish (NFE)

AF:

0.000105

AC:

AN:

856716

Other (OTH)

AF:

0.0000548

AC:

AN:

36464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000748

AC:

AN:

147038

Hom.:

Cov.:

AF XY:

0.0000558

AC XY:

AN XY:

71712

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40552

American (AMR)

AF:

0.0000671

AC:

AN:

14898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

5022

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000136

AC:

AN:

66120

Other (OTH)

AF:

0.00

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.52C>T (p.R18C) alteration is located in exon 1 (coding exon 1) of the STRN4 gene. This alteration results from a C to T substitution at nucleotide position 52, causing the arginine (R) at amino acid position 18 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;N

PhyloP100

1.2

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.65

N;N

REVEL

Benign

0.21

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.096

T;T

Polyphen

0.98

D;.

Vest4

0.18

MutPred

0.21

Loss of methylation at R18 (P = 0.0357);Loss of methylation at R18 (P = 0.0357);

MVP

0.30

MPC

1.3

ClinPred

0.83

GERP RS

2.4

PromoterAI

-0.080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.15

gMVP

0.41

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-46746379-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over