chr7-128849992-C-A

Variant names:

• chr7-128849992-C-A
• rs745650222
• NM_001458.5:c.5216C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001458.5(FLNC):​c.5216C>A​(p.Pro1739Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000627 in 1,434,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. P1739L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.37
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15373614).
• BP6: Variant 7-128849992-C-A is Benign according to our data. Variant chr7-128849992-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 648422.
• BS2: High AC in GnomAdExome4 at 9 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.5216C>A	p.Pro1739Gln	missense	Exon 31 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.5200-392C>A		intron	N/A	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.*170G>T		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5216C>A	p.Pro1739Gln	missense	Exon 31 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.5200-392C>A		intron	N/A	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.5216C>A	p.Pro1739Gln	missense	Exon 31 of 47	ENSP00000519472.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000972 AC: 2 AN: 205716 AF XY: 0.0000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.00000627 AC: 9 AN: 1434568 Hom.: 0 Cov.: 32 AF XY: 0.00000702 AC XY: 5 AN XY: 712336

African (AFR) AF: 0.00 AC: 0 AN: 33210

American (AMR) AF: 0.00 AC: 0 AN: 42216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 38874

South Asian (SAS) AF: 0.00 AC: 0 AN: 83050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42150

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103936

Other (OTH) AF: 0.0000335 AC: 2 AN: 59694

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000517 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.25
Sift	Benign	0.30	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.42
MutPred		0.31		Loss of glycosylation at P1739 (P = 0.0235)
MVP		0.41
MPC		0.26
ClinPred		0.086	T
GERP RS		4.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.028
gMVP		0.32
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs745650222; hg19: chr7-128490046;