dbSNP rs79790270: FLNC:c.5669-12C>T (chr7-128851443-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001458.5(FLNC):c.5669-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,613,920 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 93 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1057 hom. )

Consequence

FLNC
NM_001458.5 intron

Scores

Splicing: ADA: 0.0003501

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0410

Publications

2 publications found

Variant links:

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

FLNC links:

FLNC-AS1 (HGNC:53474): (FLNC antisense RNA 1)

FLNC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 7-128851443-C-T is Benign according to our data. Variant chr7-128851443-C-T is described in ClinVar as Benign. ClinVar VariationId is 258149.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 = 0.0275 (4189/152324) while in subpopulation NFE AF = 0.0377 (2567/68028). AF 95% confidence interval is 0.0365. There are 93 homozygotes in GnomAd4. There are 2170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4189 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLNC	NM_001458.5	MANE Select	c.5669-12C>T	intron	N/A	NP_001449.3	Q14315-1
FLNC	NM_001127487.2		c.5570-12C>T	intron	N/A	NP_001120959.1	Q14315-2
FLNC-AS1	NR_149055.1		n.273G>A	non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5669-12C>T	intron	N/A	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6	TSL:1	c.5570-12C>T	intron	N/A	ENSP00000344002.6	Q14315-2
FLNC	ENST00000950263.1		c.5567-12C>T	intron	N/A	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4190

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00644

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.0811

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0377

Gnomad OTH

AF:

0.0181

GnomAD2 exomes

AF:

0.0312

AC:

7794

AN:

249420

AF XY:

0.0318

show subpopulations

Gnomad AFR exome

AF:

0.00594

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0765

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0343

AC:

50078

AN:

1461596

Hom.:

1057

Cov.:

AF XY:

0.0346

AC XY:

25148

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00469

AC:

157

AN:

33480

American (AMR)

AF:

0.0106

AC:

475

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0192

AC:

502

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0311

AC:

2682

AN:

86258

European-Finnish (FIN)

AF:

0.0710

AC:

3771

AN:

53144

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0367

AC:

40775

AN:

1112000

Other (OTH)

AF:

0.0269

AC:

1623

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2989

5978

8966

11955

14944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1462

2924

4386

5848

7310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0275

AC:

4189

AN:

152324

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2170

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00642

AC:

267

AN:

41564

American (AMR)

AF:

0.0146

AC:

223

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5194

South Asian (SAS)

AF:

0.0309

AC:

149

AN:

4826

European-Finnish (FIN)

AF:

0.0811

AC:

861

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0377

AC:

2567

AN:

68028

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

217

435

652

870

1087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0318

Hom.:

Bravo

AF:

0.0210

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (2)

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;na:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.4

(source)

DANN

Benign

0.74

PhyloP100

-0.041

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00035

dbscSNV1_RF

Benign

0.030

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over