rs34422412

Variant names:

• chr7-128854456-A-G
• rs34422412
• NM_001458.5:c.6771A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-128854456-A-G
• chr7-128854456-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.6771A>G​(p.Pro2257Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,609,842 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2257P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -8.54
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-128854456-A-G is Benign according to our data. Variant chr7-128854456-A-G is described in ClinVar as Benign. ClinVar VariationId is 129095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00784 (1195/152370) while in subpopulation AFR AF = 0.0264 (1098/41584). AF 95% confidence interval is 0.0251. There are 14 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1195 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.6771A>G	p.Pro2257Pro	synonymous	Exon 41 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.6672A>G	p.Pro2224Pro	synonymous	Exon 40 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.103-1059T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.6771A>G	p.Pro2257Pro	synonymous	Exon 41 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.6672A>G	p.Pro2224Pro	synonymous	Exon 40 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.6669A>G	p.Pro2223Pro	synonymous	Exon 40 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00782 AC: 1191 AN: 152252 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00225 AC: 535 AN: 237306 AF XY: 0.00166

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000347

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.00104 AC: 1511 AN: 1457472 Hom.: 15 Cov.: 33 AF XY: 0.000958 AC XY: 694 AN XY: 724736

African (AFR) AF: 0.0274 AC: 917 AN: 33418

American (AMR) AF: 0.00274 AC: 121 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000351 AC: 30 AN: 85376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52610

Middle Eastern (MID) AF: 0.00250 AC: 14 AN: 5590

European-Non Finnish (NFE) AF: 0.000258 AC: 287 AN: 1110572

Other (OTH) AF: 0.00233 AC: 140 AN: 60182

GnomAD4 genome AF: 0.00784 AC: 1195 AN: 152370 Hom.: 14 Cov.: 33 AF XY: 0.00735 AC XY: 548 AN XY: 74516

African (AFR) AF: 0.0264 AC: 1098 AN: 41584

American (AMR) AF: 0.00294 AC: 45 AN: 15312

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

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68026

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00388 Hom.: 9

Bravo AF: 0.00950

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	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	-0.80
CADD	Benign	0.17
DANN	Benign	0.58
PhyloP100		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=56/44	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: rs34422412; hg19: chr7-128494510;