rs200502811

Variant names:

• chr7-128858348-T-C
• rs200502811
• NM_001458.5:c.8003T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001458.5(FLNC):​c.8003T>C​(p.Met2668Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,550,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2668V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 7.97
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009941429).
• BP6: Variant 7-128858348-T-C is Benign according to our data. Variant chr7-128858348-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211026.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00264 (401/151714) while in subpopulation AFR AF = 0.00927 (383/41332). AF 95% confidence interval is 0.0085. There are 1 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 401 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.8003T>C	p.Met2668Thr	missense	Exon 48 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.7904T>C	p.Met2635Thr	missense	Exon 47 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.102+4177A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.8003T>C	p.Met2668Thr	missense	Exon 48 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.7904T>C	p.Met2635Thr	missense	Exon 47 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.7901T>C	p.Met2634Thr	missense	Exon 47 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 399 AN: 151596 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000587 AC: 136 AN: 231720 AF XY: 0.000405

Gnomad AFR exome AF: 0.00943

Gnomad AMR exome AF: 0.0000916

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000349

GnomAD4 exome AF: 0.000262 AC: 366 AN: 1399020 Hom.: 0 Cov.: 24 AF XY: 0.000203 AC XY: 142 AN XY: 697996

African (AFR) AF: 0.0104 AC: 331 AN: 31802

American (AMR) AF: 0.000160 AC: 7 AN: 43620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25636

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.0000594 AC: 5 AN: 84108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4732

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058674

Other (OTH) AF: 0.000378 AC: 22 AN: 58154

GnomAD4 genome AF: 0.00264 AC: 401 AN: 151714 Hom.: 1 Cov.: 32 AF XY: 0.00262 AC XY: 194 AN XY: 74102

African (AFR) AF: 0.00927 AC: 383 AN: 41332

American (AMR) AF: 0.000852 AC: 13 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67856

Other (OTH) AF: 0.00143 AC: 3 AN: 2098

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00302

ESP6500AA AF: 0.00928 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000704 AC: 85

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.064
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.34	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.20	B
Vest4		0.70
MVP		0.61
MPC		1.1
ClinPred		0.13	T
GERP RS		4.6
Varity_R		0.85
gMVP		0.68
Mutation Taster		=35/65	disease causing

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: rs200502811; hg19: chr7-128498402;