chr7-128857161-G-C

Variant names:

• chr7-128857161-G-C
• rs777724201
• NM_001458.5:c.7605G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000325888.13(FLNC):​c.7605G>C​(p.Ser2535Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2535S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLNC ENST00000325888.13 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.29
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=-5.28 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000325888.13. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.7605G>C	p.Ser2535Ser	synonymous	Exon 46 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.7506G>C	p.Ser2502Ser	synonymous	Exon 45 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.103-3764C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7605G>C	p.Ser2535Ser	synonymous	Exon 46 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.7506G>C	p.Ser2502Ser	synonymous	Exon 45 of 47	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.7467G>C	p.Ser2489Ser	synonymous	Exon 45 of 47	ENSP00000519472.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000450 AC: 111 AN: 246620 AF XY: 0.000268

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000471

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.000166

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000322 AC: 47 AN: 1461098 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 726848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000682 AC: 36 AN: 52794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.0000828 AC: 5 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.071
DANN	Benign	0.55
PhyloP100		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs777724201; hg19: chr7-128497215;