7-128850038-C-T

Variant names:

• chr7-128850038-C-T
• rs369165766
• NM_001458.5:c.5262C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.5262C>T​(p.Tyr1754Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,552,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.526
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 7-128850038-C-T is Benign according to our data. Variant chr7-128850038-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.526 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (186/152332) while in subpopulation AFR AF = 0.00426 (177/41574). AF 95% confidence interval is 0.00374. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 186 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.5262C>T	p.Tyr1754Tyr	synonymous	Exon 31 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.5200-346C>T		intron	N/A	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.*124G>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.5262C>T	p.Tyr1754Tyr	synonymous	Exon 31 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.5200-346C>T		intron	N/A	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.5262C>T	p.Tyr1754Tyr	synonymous	Exon 31 of 47	ENSP00000519472.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000365 AC: 57 AN: 156010 AF XY: 0.000354

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000306

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000147 AC: 206 AN: 1400386 Hom.: 0 Cov.: 32 AF XY: 0.000146 AC XY: 101 AN XY: 692648

African (AFR) AF: 0.00496 AC: 160 AN: 32254

American (AMR) AF: 0.000214 AC: 8 AN: 37336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25274

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36702

South Asian (SAS) AF: 0.0000623 AC: 5 AN: 80242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000828 AC: 9 AN: 1086828

Other (OTH) AF: 0.000394 AC: 23 AN: 58444

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00111 AC XY: 83 AN XY: 74488

African (AFR) AF: 0.00426 AC: 177 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.00154

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.3
DANN	Benign	0.94
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs369165766; hg19: chr7-128490092; COSMIC: COSV100368808; COSMIC: COSV100368808;