rs199880128

Variant names:

• chr7-128855248-C-T
• rs199880128
• NM_001458.5:c.7185C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.7185C>T​(p.Ser2395Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,613,912 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.106
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-128855248-C-T is Benign according to our data. Variant chr7-128855248-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.106 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00084 (128/152322) while in subpopulation NFE AF = 0.00147 (100/68024). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 128 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.7185C>T	p.Ser2395Ser	synonymous	Exon 43 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.7086C>T	p.Ser2362Ser	synonymous	Exon 42 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.103-1851G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7185C>T	p.Ser2395Ser	synonymous	Exon 43 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.7086C>T	p.Ser2362Ser	synonymous	Exon 42 of 47	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.7047C>T	p.Ser2349Ser	synonymous	Exon 42 of 47	ENSP00000519472.1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000668 AC: 167 AN: 249912 AF XY: 0.000620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.000997

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000649 AC: 949 AN: 1461590 Hom.: 2 Cov.: 31 AF XY: 0.000674 AC XY: 490 AN XY: 727136

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000744 AC: 827 AN: 1111838

Other (OTH) AF: 0.000397 AC: 24 AN: 60386

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.000480

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	FLNC-related disorder (1)
-	-	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	-0.46
CADD	Benign	7.5
DANN	Benign	0.88
PhyloP100		-0.11
Mutation Taster		=99/1	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: rs199880128; hg19: chr7-128495302;