rs34972246

Variant names:

• chr7-128841524-A-C
• rs34972246
• NM_001458.5:c.2078A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.2078A>C​(p.Asp693Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,614,124 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (20 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.86
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P, Ambry Genetics
• myofibrillar myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015948474).
• BP6: Variant 7-128841524-A-C is Benign according to our data. Variant chr7-128841524-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258129.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 = 0.00286 (436/152298) while in subpopulation NFE AF = 0.00432 (294/68016). AF 95% confidence interval is 0.00392. There are 2 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 436 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.2078A>C	p.Asp693Ala	missense	Exon 13 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.2078A>C	p.Asp693Ala	missense	Exon 13 of 47	NP_001120959.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.2078A>C	p.Asp693Ala	missense	Exon 13 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.2078A>C	p.Asp693Ala	missense	Exon 13 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.2078A>C	p.Asp693Ala	missense	Exon 13 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00347 AC: 867 AN: 249582 AF XY: 0.00344

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.00514

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00466 AC: 6819 AN: 1461826 Hom.: 20 Cov.: 33 AF XY: 0.00446 AC XY: 3247 AN XY: 727228

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 261 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86258

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53390

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00523 AC: 5820 AN: 1111976

Other (OTH) AF: 0.00553 AC: 334 AN: 60394

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74470

African (AFR) AF: 0.000962 AC: 40 AN: 41562

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00432 AC: 294 AN: 68016

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00383 Hom.: 8

Bravo AF: 0.00286

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00123 AC: 5

ESP6500EA AF: 0.00536 AC: 45

ExAC AF: 0.00369 AC: 447

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00516

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.92	P
Vest4		0.50
MVP		0.79
MPC		0.99
ClinPred		0.053	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.86
gMVP		0.81
Mutation Taster		=67/33	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: rs34972246; hg19: chr7-128481578; COSMIC: COSV57962148;