chr7-128850081-C-T

Variant names:

• chr7-128850081-C-T
• rs773294846
• NM_001458.5:c.5298+7C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001458.5(FLNC):​c.5298+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,527,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: FLNC NM_001458.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006099
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-128850081-C-T is Benign according to our data. Variant chr7-128850081-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 513475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 20 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.5298+7C>T		splice_region intron	N/A	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.5200-303C>T		intron	N/A	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.*81G>A		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5298+7C>T		splice_region intron	N/A	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.5200-303C>T		intron	N/A	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.5197-303C>T		intron	N/A	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000424 AC: 6 AN: 141600 AF XY: 0.0000653

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 20 AN: 1375510 Hom.: 0 Cov.: 30 AF XY: 0.0000162 AC XY: 11 AN XY: 679942

African (AFR) AF: 0.0000317 AC: 1 AN: 31508

American (AMR) AF: 0.00 AC: 0 AN: 35834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 35840

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35548

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5570

European-Non Finnish (NFE) AF: 0.0000131 AC: 14 AN: 1069258

Other (OTH) AF: 0.0000347 AC: 2 AN: 57648

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000767 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.62
CADD	Benign	8.9
DANN	Benign	0.83
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.0		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: rs773294846; hg19: chr7-128490135;