7-128858364-C-G

Variant names:

• chr7-128858364-C-G
• rs112180788
• NM_001458.5:c.8019C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000325888.13(FLNC):​c.8019C>G​(p.His2673Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,571,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H2673H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: FLNC ENST00000325888.13 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -3.12
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene.

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.8019C>G	p.His2673Gln	missense	Exon 48 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.7920C>G	p.His2640Gln	missense	Exon 47 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.102+4161G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.8019C>G	p.His2673Gln	missense	Exon 48 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.7920C>G	p.His2640Gln	missense	Exon 47 of 47	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.7881C>G	p.His2627Gln	missense	Exon 47 of 47	ENSP00000519472.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151790 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238780 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000929

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000197 AC: 28 AN: 1420122 Hom.: 0 Cov.: 26 AF XY: 0.0000212 AC XY: 15 AN XY: 708322

African (AFR) AF: 0.00 AC: 0 AN: 32306

American (AMR) AF: 0.00 AC: 0 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 84778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4992

European-Non Finnish (NFE) AF: 0.0000251 AC: 27 AN: 1076622

Other (OTH) AF: 0.0000170 AC: 1 AN: 58852

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151790 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74076

African (AFR) AF: 0.00 AC: 0 AN: 41292

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	0.21
DANN	Benign	0.87
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.3	L
PhyloP100		-3.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.42		Gain of loop (P = 0.1069)
MVP		0.87
MPC		1.6
ClinPred		0.57	D
GERP RS		-5.6
Varity_R		0.82
gMVP		0.62
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs112180788; hg19: chr7-128498418;