rs3734972

Variant names:

• chr7-128830784-C-T
• rs3734972
• NM_001458.5:c.147C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001458.5(FLNC):​c.147C>T​(p.His49His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,612,946 control chromosomes in the GnomAD database, including 6,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (714 hom., cov: 33)
  • Exomes 𝑓: 0.088 (5983 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.787
• Publications: 16 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: G2P, ClinGen, Ambry Genetics
• myofibrillar myopathy

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

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

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

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-128830784-C-T is Benign according to our data. Variant chr7-128830784-C-T is described in ClinVar as Benign. ClinVar VariationId is 129081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.787 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.147C>T	p.His49His	synonymous	Exon 1 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.147C>T	p.His49His	synonymous	Exon 1 of 47	NP_001120959.1	Q14315-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.147C>T	p.His49His	synonymous	Exon 1 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.147C>T	p.His49His	synonymous	Exon 1 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.147C>T	p.His49His	synonymous	Exon 1 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14287 AN: 152184 Hom.: 712 Cov.: 33

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.0985

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0940 AC: 23381 AN: 248698 AF XY: 0.0929

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0866

Gnomad ASJ exome AF: 0.0908

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.0835

Gnomad NFE exome AF: 0.0861

Gnomad OTH exome AF: 0.0943

GnomAD4 exome AF: 0.0884 AC: 129166 AN: 1460644 Hom.: 5983 Cov.: 33 AF XY: 0.0887 AC XY: 64470 AN XY: 726626

African (AFR) AF: 0.102 AC: 3406 AN: 33476

American (AMR) AF: 0.0898 AC: 4011 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 2373 AN: 26124

East Asian (EAS) AF: 0.183 AC: 7276 AN: 39684

South Asian (SAS) AF: 0.0876 AC: 7554 AN: 86242

European-Finnish (FIN) AF: 0.0829 AC: 4349 AN: 52486

Middle Eastern (MID) AF: 0.0846 AC: 488 AN: 5768

European-Non Finnish (NFE) AF: 0.0848 AC: 94262 AN: 1111824

Other (OTH) AF: 0.0902 AC: 5447 AN: 60370

GnomAD4 genome AF: 0.0939 AC: 14307 AN: 152302 Hom.: 714 Cov.: 33 AF XY: 0.0939 AC XY: 6995 AN XY: 74478

African (AFR) AF: 0.0976 AC: 4057 AN: 41552

American (AMR) AF: 0.0881 AC: 1348 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0985 AC: 342 AN: 3472

East Asian (EAS) AF: 0.191 AC: 989 AN: 5172

South Asian (SAS) AF: 0.0979 AC: 473 AN: 4832

European-Finnish (FIN) AF: 0.0844 AC: 897 AN: 10626

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0865 AC: 5887 AN: 68026

Other (OTH) AF: 0.108 AC: 229 AN: 2112

Alfa AF: 0.0898 Hom.: 1099

Bravo AF: 0.0949

Asia WGS AF: 0.145 AC: 506 AN: 3478

EpiCase AF: 0.0921

EpiControl AF: 0.0885

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.7
DANN	Benign	0.97
PhyloP100		0.79
PromoterAI		-0.085	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs3734972; hg19: chr7-128470838; COSMIC: COSV57952752;