7-128852937-C-T

Variant names:

• chr7-128852937-C-T
• rs559639511
• NM_001458.5:c.6114C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001458.5(FLNC):​c.6114C>T​(p.Ile2038Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,598 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.66
• Publications: 1 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 7-128852937-C-T is Benign according to our data. Variant chr7-128852937-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 539487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.66 with no splicing effect.
• BS2: High AC in GnomAd4 at 9 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.6114C>T	p.Ile2038Ile	synonymous	Exon 37 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.6015C>T	p.Ile2005Ile	synonymous	Exon 36 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.215+348G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.6114C>T	p.Ile2038Ile	synonymous	Exon 37 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.6015C>T	p.Ile2005Ile	synonymous	Exon 36 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.6012C>T	p.Ile2004Ile	synonymous	Exon 36 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000152 AC: 38 AN: 249348 AF XY: 0.000170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000946

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461310 Hom.: 0 Cov.: 33 AF XY: 0.0000729 AC XY: 53 AN XY: 726956

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1112004

Other (OTH) AF: 0.000232 AC: 14 AN: 60390

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000869

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.9
DANN	Benign	0.84
PhyloP100		-5.7
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs559639511; hg19: chr7-128492991; COSMIC: COSV57964267;