rs769791248

Variant names:

• chr7-128837236-C-A
• rs769791248
• NM_001458.5:c.678C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128837236-C-A
• chr7-128837236-C-G
• chr7-128837236-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001458.5(FLNC):​c.678C>A​(p.Asp226Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,435,768 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D226N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.90
• Publications: 0 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, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001458.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22151372).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.678C>A	p.Asp226Glu	missense	Exon 3 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.678C>A	p.Asp226Glu	missense	Exon 3 of 47	NP_001120959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.678C>A	p.Asp226Glu	missense	Exon 3 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.678C>A	p.Asp226Glu	missense	Exon 3 of 47	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.678C>A	p.Asp226Glu	missense	Exon 3 of 47	ENSP00000519472.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1435768 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 711584

African (AFR) AF: 0.00 AC: 0 AN: 33002

American (AMR) AF: 0.00 AC: 0 AN: 41794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25626

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.00 AC: 0 AN: 82286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099616

Other (OTH) AF: 0.00 AC: 0 AN: 59366

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.5
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.66	N
PhyloP100		-1.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.086	T
Sift4G	Benign	0.23	T
Polyphen		0.65	P
Vest4		0.48
MutPred		0.56		Gain of catalytic residue at W228 (P = 0.1101)
MVP		0.48
MPC		2.1
ClinPred		0.90	D
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.25
gMVP		0.58
Mutation Taster		=39/61	disease causing

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: rs769791248; hg19: chr7-128477290;