rs2291567

Variant names:

• chr7-128843173-T-C
• rs2291567
• NM_001458.5:c.2551-56T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-128843173-T-C
• chr7-128843173-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001458.5(FLNC):​c.2551-56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,501,336 control chromosomes in the GnomAD database, including 34,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7436 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26920 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.659
• Publications: 11 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=-0.89).
• BP6: Variant 7-128843173-T-C is Benign according to our data. Variant chr7-128843173-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.2551-56T>C		intron_variant	Intron 16 of 47	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.2551-56T>C		intron_variant	Intron 16 of 46		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.2551-56T>C		intron_variant	Intron 16 of 47	1	NM_001458.5	ENSP00000327145.8

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41124 AN: 151938 Hom.: 7414 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.185 AC: 249745 AN: 1349280 Hom.: 26920 Cov.: 24 AF XY: 0.186 AC XY: 124460 AN XY: 668938

African (AFR) AF: 0.504 AC: 15466 AN: 30698

American (AMR) AF: 0.203 AC: 7330 AN: 36022

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3191 AN: 24936

East Asian (EAS) AF: 0.462 AC: 16553 AN: 35816

South Asian (SAS) AF: 0.256 AC: 20116 AN: 78718

European-Finnish (FIN) AF: 0.143 AC: 7037 AN: 49346

Middle Eastern (MID) AF: 0.135 AC: 648 AN: 4786

European-Non Finnish (NFE) AF: 0.163 AC: 167928 AN: 1032638

Other (OTH) AF: 0.204 AC: 11476 AN: 56320

GnomAD4 genome AF: 0.271 AC: 41182 AN: 152056 Hom.: 7436 Cov.: 33 AF XY: 0.268 AC XY: 19915 AN XY: 74352

African (AFR) AF: 0.502 AC: 20811 AN: 41444

American (AMR) AF: 0.182 AC: 2784 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3468

East Asian (EAS) AF: 0.468 AC: 2413 AN: 5156

South Asian (SAS) AF: 0.281 AC: 1356 AN: 4818

European-Finnish (FIN) AF: 0.130 AC: 1376 AN: 10600

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11320 AN: 67966

Other (OTH) AF: 0.251 AC: 530 AN: 2114

Alfa AF: 0.191 Hom.: 5580

Bravo AF: 0.285

Asia WGS AF: 0.383 AC: 1330 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.43
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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: rs2291567; hg19: chr7-128483227; COSMIC: COSV57955032; COSMIC: COSV57955032;