NM_001458.5:c.5042C>G

Variant names:

• chr7-128849421-C-G
• rs193159707
• NM_001458.5:c.5042C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.5042C>G​(p.Thr1681Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,614,200 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1681M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.91
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011175424).
• BP6: Variant 7-128849421-C-G is Benign according to our data. Variant chr7-128849421-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00182 (277/152340) while in subpopulation AFR AF = 0.00563 (234/41576). AF 95% confidence interval is 0.00504. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 277 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.5042C>G	p.Thr1681Arg	missense	Exon 30 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.5042C>G	p.Thr1681Arg	missense	Exon 30 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.5042C>G	p.Thr1681Arg	missense	Exon 30 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.5042C>G	p.Thr1681Arg	missense	Exon 30 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.5039C>G	p.Thr1680Arg	missense	Exon 30 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000541 AC: 135 AN: 249518 AF XY: 0.000392

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1461860 Hom.: 4 Cov.: 37 AF XY: 0.000243 AC XY: 177 AN XY: 727226

African (AFR) AF: 0.00756 AC: 253 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1112012

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74494

African (AFR) AF: 0.00563 AC: 234 AN: 41576

American (AMR) AF: 0.00216 AC: 33 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.00213

ESP6500AA AF: 0.00411 AC: 18

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000569 AC: 69

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	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	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.2	L
PhyloP100		1.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.014	D
Sift4G	Benign	0.59	T
Polyphen		0.90	P
Vest4		0.46
MVP		0.43
MPC		0.41
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.39
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193159707; hg19: chr7-128489475;