rs201333104

Variant names:

• chr7-128852998-G-A
• rs201333104
• NM_001458.5:c.6175G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.6175G>A​(p.Val2059Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,380 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V2059V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.56
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021668077).
• BP6: Variant 7-128852998-G-A is Benign according to our data. Variant chr7-128852998-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000722 (110/152280) while in subpopulation NFE AF = 0.00116 (79/68010). AF 95% confidence interval is 0.000955. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 110 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.6175G>A	p.Val2059Met	missense	Exon 37 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.6076G>A	p.Val2026Met	missense	Exon 36 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.215+287C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.6175G>A	p.Val2059Met	missense	Exon 37 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.6076G>A	p.Val2026Met	missense	Exon 36 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.6073G>A	p.Val2025Met	missense	Exon 36 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000870 AC: 216 AN: 248402 AF XY: 0.000926

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.00127 AC: 1858 AN: 1461100 Hom.: 1 Cov.: 33 AF XY: 0.00129 AC XY: 935 AN XY: 726868

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.000361 AC: 19 AN: 52648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00155 AC: 1728 AN: 1112002

Other (OTH) AF: 0.00114 AC: 69 AN: 60388

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74460

African (AFR) AF: 0.000385 AC: 16 AN: 41548

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.000763

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.00112 AC: 135

EpiCase AF: 0.00158

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Distal myopathy with posterior leg and anterior hand involvement (1)
-	-	1	FLNC-related disorder (1)
-	-	1	Hypertrophic cardiomyopathy 26 (1)
-	-	1	Myofibrillar myopathy 5 (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
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.27	N
PhyloP100		1.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.48	N
REVEL	Uncertain	0.33
Sift	Benign	0.13	T
Sift4G	Benign	0.24	T
Polyphen		0.044	B
Vest4		0.33
MVP		0.43
MPC		1.2
ClinPred		0.014	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.29
Mutation Taster		=83/17	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: rs201333104; hg19: chr7-128493052; COSMIC: COSV57958194;