chr7-128835339-C-G

Variant names:

• chr7-128835339-C-G
• NM_001458.5:c.366C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001458.5(FLNC):​c.366C>G​(p.Ile122Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I122I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Calponin-homology (CH) 1 (size 106) in uniprot entity FLNC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001458.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.366C>G	p.Ile122Met	missense_variant	Exon 2 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.366C>G	p.Ile122Met	missense_variant	Exon 2 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.366C>G	p.Ile122Met	missense_variant	Exon 2 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.366C>G	p.Ile122Met	missense_variant	Exon 2 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461434 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.017
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.83		Loss of catalytic residue at L127 (P = 0.0932);Loss of catalytic residue at L127 (P = 0.0932);
MVP		0.81
MPC		2.2
ClinPred		1.0	D
GERP RS		0.37
Varity_R		0.74
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128475393;