rs1554401837

Variant names:

• chr7-128856894-GGTCCTGGGCTCGA-G
• rs1554401837
• NM_001458.5:c.7536_7548delTCCTGGGCTCGAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001458.5(FLNC):​c.7536_7548delTCCTGGGCTCGAG​(p.Pro2513GlufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.97
• 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-128856894-GGTCCTGGGCTCGA-G is Pathogenic according to our data. Variant chr7-128856894-GGTCCTGGGCTCGA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 539437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.7536_7548delTCCTGGGCTCGAG	p.Pro2513GlufsTer12	frameshift	Exon 45 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.7437_7449delTCCTGGGCTCGAG	p.Pro2480GlufsTer12	frameshift	Exon 44 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.103-3510_103-3498delTCGAGCCCAGGAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7536_7548delTCCTGGGCTCGAG	p.Pro2513GlufsTer12	frameshift	Exon 45 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.7437_7449delTCCTGGGCTCGAG	p.Pro2480GlufsTer12	frameshift	Exon 44 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.7434_7446delTCCTGGGCTCGAG	p.Pro2479GlufsTer12	frameshift	Exon 44 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554401837; hg19: chr7-128496948;