chr7-128858030-C-T

Variant names:

• chr7-128858030-C-T
• rs749737805
• NM_001458.5:c.7803C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.7803C>T​(p.His2601His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,552,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.77
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-128858030-C-T is Benign according to our data. Variant chr7-128858030-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 472181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000112 (17/152204) while in subpopulation AMR AF = 0.00105 (16/15288). AF 95% confidence interval is 0.000656. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 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.7803C>T	p.His2601His	synonymous	Exon 47 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.7704C>T	p.His2568His	synonymous	Exon 46 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.102+4495G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7803C>T	p.His2601His	synonymous	Exon 47 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.7704C>T	p.His2568His	synonymous	Exon 46 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.7701C>T	p.His2567His	synonymous	Exon 46 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000464 AC: 8 AN: 172524 AF XY: 0.0000431

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000610

Gnomad NFE exome AF: 0.0000428

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000379 AC: 53 AN: 1400020 Hom.: 0 Cov.: 28 AF XY: 0.0000417 AC XY: 29 AN XY: 696050

African (AFR) AF: 0.00 AC: 0 AN: 32450

American (AMR) AF: 0.0000981 AC: 4 AN: 40794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38166

South Asian (SAS) AF: 0.00 AC: 0 AN: 81108

European-Finnish (FIN) AF: 0.0000392 AC: 2 AN: 51002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.0000431 AC: 46 AN: 1067322

Other (OTH) AF: 0.0000172 AC: 1 AN: 58196

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00105 AC: 16 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Likely benign

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.4
DANN	Benign	0.89
PhyloP100		2.8
Mutation Taster		=100/0	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: rs749737805; hg19: chr7-128498084;