7-128830606-T-TAGCCCCGGCCGCACCCCC

Variant names:

• chr7-128830606-T-TAGCCCCGGCCGCACCCCC
• rs749265933
• NM_001458.5:c.-26_-9dupCGGCCGCACCCCCAGCCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001458.5(FLNC):​c.-26_-9dupCGGCCGCACCCCCAGCCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,601,736 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: FLNC NM_001458.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:3
• Conservation: PhyloP100: -2.49
• 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 -9 ACMG points.

• BP6: Variant 7-128830606-T-TAGCCCCGGCCGCACCCCC is Benign according to our data. Variant chr7-128830606-T-TAGCCCCGGCCGCACCCCC is described in ClinVar as [Likely_benign]. Clinvar id is 1299957.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000441 (67/151850) while in subpopulation NFE AF = 0.000677 (46/67902). AF 95% confidence interval is 0.000522. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.-26_-9dupCGGCCGCACCCCCAGCCC		5_prime_UTR_variant	Exon 1 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.-26_-9dupCGGCCGCACCCCCAGCCC		5_prime_UTR_variant	Exon 1 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.-26_-9dupCGGCCGCACCCCCAGCCC		5_prime_UTR_variant	Exon 1 of 48	1	NM_001458.5	ENSP00000327145.8

Frequencies

GnomAD3 genomes AF: 0.000442 AC: 67 AN: 151732 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000291 AC: 67 AN: 230294 AF XY: 0.000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00178

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000496

Gnomad NFE exome AF: 0.000385

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000319 AC: 463 AN: 1449886 Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 223 AN XY: 721420

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.00200 AC: 52 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85568

European-Finnish (FIN) AF: 0.00144 AC: 74 AN: 51452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000283 AC: 313 AN: 1104416

Other (OTH) AF: 0.000401 AC: 24 AN: 59902

GnomAD4 genome AF: 0.000441 AC: 67 AN: 151850 Hom.: 0 Cov.: 33 AF XY: 0.000404 AC XY: 30 AN XY: 74220

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000677 AC: 46 AN: 67902

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00150 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

FLNC-related disorder Benign:1

Apr 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.5
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs749265933; hg19: chr7-128470660;