rs370589662

Variant names:

• chr7-128854191-C-G
• rs370589662
• NM_001458.5:c.6702C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-128854191-C-G
• chr7-128854191-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001458.5(FLNC):​c.6702C>G​(p.Phe2234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,455,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F2234F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.729
• 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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 7-128854191-C-G is Benign according to our data. Variant chr7-128854191-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1446278.
• BS2: High AC in GnomAdExome4 at 23 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.6702C>G	p.Phe2234Leu	missense	Exon 40 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.6603C>G	p.Phe2201Leu	missense	Exon 39 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.103-794G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.6702C>G	p.Phe2234Leu	missense	Exon 40 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.6603C>G	p.Phe2201Leu	missense	Exon 39 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.6600C>G	p.Phe2200Leu	missense	Exon 39 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 241936 AF XY: 0.00000756

Gnomad AFR exome AF: 0.0000673

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1455840 Hom.: 0 Cov.: 34 AF XY: 0.00000829 AC XY: 6 AN XY: 723710

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1109542

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.77
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.73
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.61
Sift	Benign	0.72	T
Sift4G	Uncertain	0.010	D
Polyphen		0.42	B
Vest4		0.79
MutPred		0.79		Loss of sheet (P = 0.1158)
MVP		0.92
MPC		0.83
ClinPred		0.085	T
GERP RS		-4.5
Varity_R		0.042
gMVP		0.59
Mutation Taster		=49/51	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: rs370589662; hg19: chr7-128494245;