rs34180031

Variant names:

• chr7-128846037-C-T
• rs34180031
• NM_001458.5:c.3838C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-128846037-C-T
• chr7-128846037-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.3838C>T​(p.Leu1280Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 1,613,884 control chromosomes in the GnomAD database, including 1,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (106 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1070 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.25
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 7-128846037-C-T is Benign according to our data. Variant chr7-128846037-C-T is described in ClinVar as Benign. ClinVar VariationId is 129087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0333 (5075/152254) while in subpopulation NFE AF = 0.0379 (2578/68002). AF 95% confidence interval is 0.0367. There are 106 homozygotes in GnomAd4. There are 2600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5075 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.3838C>T	p.Leu1280Leu	synonymous	Exon 22 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.3838C>T	p.Leu1280Leu	synonymous	Exon 22 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.3838C>T	p.Leu1280Leu	synonymous	Exon 22 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.3838C>T	p.Leu1280Leu	synonymous	Exon 22 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.3835C>T	p.Leu1279Leu	synonymous	Exon 22 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5067 AN: 152138 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0309

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0325 AC: 8100 AN: 248950 AF XY: 0.0329

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0764

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0349 AC: 50961 AN: 1461630 Hom.: 1070 Cov.: 34 AF XY: 0.0351 AC XY: 25533 AN XY: 727120

African (AFR) AF: 0.0249 AC: 835 AN: 33478

American (AMR) AF: 0.0114 AC: 508 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 502 AN: 26132

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0312 AC: 2691 AN: 86254

European-Finnish (FIN) AF: 0.0708 AC: 3770 AN: 53212

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.0367 AC: 40815 AN: 1111974

Other (OTH) AF: 0.0289 AC: 1745 AN: 60394

GnomAD4 genome AF: 0.0333 AC: 5075 AN: 152254 Hom.: 106 Cov.: 32 AF XY: 0.0349 AC XY: 2600 AN XY: 74432

African (AFR) AF: 0.0261 AC: 1086 AN: 41546

American (AMR) AF: 0.0176 AC: 270 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4822

European-Finnish (FIN) AF: 0.0810 AC: 860 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0379 AC: 2578 AN: 68002

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0349 Hom.: 48

Bravo AF: 0.0275

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0349

EpiControl AF: 0.0322

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	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	-0.57
CADD	Benign	7.6
DANN	Benign	0.88
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34180031; hg19: chr7-128486091;