rs71581921

Variant names:

• chr7-128842780-C-T
• rs71581921
• NM_001458.5:c.2390-14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.2390-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,612,962 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (11 hom., cov: 33)
  • Exomes 𝑓: 0.011 (115 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.189
• 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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 (BayesDel_noAF=-0.77).
• BP6: Variant 7-128842780-C-T is Benign according to our data. Variant chr7-128842780-C-T is described in ClinVar as Benign. ClinVar VariationId is 258137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00811 (1236/152330) while in subpopulation NFE AF = 0.0106 (723/68014). AF 95% confidence interval is 0.00999. There are 11 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1236 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.2390-14C>T		intron	N/A	NP_001449.3
	FLNC	NM_001127487.2		c.2390-14C>T		intron	N/A	NP_001120959.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.2390-14C>T		intron	N/A	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.2390-14C>T		intron	N/A	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.2390-14C>T		intron	N/A	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152212 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.0102 AC: 2507 AN: 246420 AF XY: 0.00979

Gnomad AFR exome AF: 0.00250

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0111 AC: 16205 AN: 1460632 Hom.: 115 Cov.: 38 AF XY: 0.0108 AC XY: 7871 AN XY: 726590

African (AFR) AF: 0.00194 AC: 65 AN: 33474

American (AMR) AF: 0.00701 AC: 313 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 532 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00123 AC: 106 AN: 86192

European-Finnish (FIN) AF: 0.0192 AC: 1010 AN: 52622

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5766

European-Non Finnish (NFE) AF: 0.0122 AC: 13596 AN: 1111754

Other (OTH) AF: 0.00916 AC: 553 AN: 60346

GnomAD4 genome AF: 0.00811 AC: 1236 AN: 152330 Hom.: 11 Cov.: 33 AF XY: 0.00824 AC XY: 614 AN XY: 74482

African (AFR) AF: 0.00281 AC: 117 AN: 41578

American (AMR) AF: 0.00666 AC: 102 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

European-Finnish (FIN) AF: 0.0184 AC: 195 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 723 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.0103 Hom.: 2

Bravo AF: 0.00744

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 (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	-0.77
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs71581921; hg19: chr7-128482834;