Genetic Variant FLNC:p.Thr2153Thr (chr7-128853812-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):c.6459C>T(p.Thr2153Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,613,588 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2153T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0034 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 169 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.91

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 7-128853812-C-T is Benign according to our data. Variant chr7-128853812-C-T is described in ClinVar as Benign. ClinVar VariationId is 197064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.91 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNC	NM_001458.5	MANE Select	c.6459C>T	p.Thr2153Thr	synonymous	Exon 39 of 48	NP_001449.3	Q14315-1
FLNC	NM_001127487.2		c.6360C>T	p.Thr2120Thr	synonymous	Exon 38 of 47	NP_001120959.1	Q14315-2
FLNC-AS1	NR_149055.1		n.103-415G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.6459C>T	p.Thr2153Thr	synonymous	Exon 39 of 48	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6	TSL:1	c.6360C>T	p.Thr2120Thr	synonymous	Exon 38 of 47	ENSP00000344002.6	Q14315-2
FLNC	ENST00000950263.1		c.6357C>T	p.Thr2119Thr	synonymous	Exon 38 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

520

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0201

Gnomad SAS

AF:

0.0579

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00823

AC:

2052

AN:

249188

AF XY:

0.00997

show subpopulations

Gnomad AFR exome

AF:

0.000453

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0173

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00507

AC:

7411

AN:

1461330

Hom.:

169

Cov.:

AF XY:

0.00630

AC XY:

4577

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000715

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0189

AC:

752

AN:

39700

South Asian (SAS)

AF:

0.0499

AC:

4304

AN:

86256

European-Finnish (FIN)

AF:

0.0000378

AC:

AN:

52882

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00173

AC:

1921

AN:

1111998

Other (OTH)

AF:

0.00624

AC:

377

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

590

1180

1771

2361

2951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00339

AC:

516

AN:

152258

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41562

American (AMR)

AF:

0.00150

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0202

AC:

104

AN:

5150

South Asian (SAS)

AF:

0.0571

AC:

275

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68008

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00102

Hom.:

Bravo

AF:

0.00171

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

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

-0.53

CADD

Benign

7.4

(source)

DANN

Benign

0.89

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(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

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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