chr7-128842905-C-T

Variant names:

• chr7-128842905-C-T
• rs75133741
• NM_001458.5:c.2501C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001458.5(FLNC):​c.2501C>T​(p.Thr834Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,052 control chromosomes in the GnomAD database, including 178 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. T834A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (166 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.67
• Publications: 9 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=0.010443568).
• BP6: Variant 7-128842905-C-T is Benign according to our data. Variant chr7-128842905-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0506 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.2501C>T	p.Thr834Met	missense	Exon 16 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.2501C>T	p.Thr834Met	missense	Exon 16 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.2501C>T	p.Thr834Met	missense	Exon 16 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.2501C>T	p.Thr834Met	missense	Exon 16 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.2501C>T	p.Thr834Met	missense	Exon 16 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152250 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00814 AC: 2029 AN: 249136 AF XY: 0.00985

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0173

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00504 AC: 7373 AN: 1461684 Hom.: 166 Cov.: 37 AF XY: 0.00626 AC XY: 4555 AN XY: 727154

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000716 AC: 32 AN: 44720

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

East Asian (EAS) AF: 0.0189 AC: 749 AN: 39698

South Asian (SAS) AF: 0.0493 AC: 4250 AN: 86252

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53240

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00174 AC: 1939 AN: 1111996

Other (OTH) AF: 0.00621 AC: 375 AN: 60394

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152368 Hom.: 12 Cov.: 33 AF XY: 0.00459 AC XY: 342 AN XY: 74508

African (AFR) AF: 0.000337 AC: 14 AN: 41586

American (AMR) AF: 0.00150 AC: 23 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0203 AC: 105 AN: 5184

South Asian (SAS) AF: 0.0561 AC: 271 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00225 Hom.: 11

Bravo AF: 0.00172

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000467 AC: 2

ESP6500EA AF: 0.00154 AC: 13

ExAC AF: 0.00893 AC: 1081

Asia WGS AF: 0.0390 AC: 137 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	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	Benign	0.065
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.45
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.25	B
Vest4		0.44
MVP		0.47
MPC		0.43
ClinPred		0.041	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.38
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75133741; hg19: chr7-128482959;