rs201149834

Variant names:

• chr7-128857346-A-G
• rs201149834
• NM_001458.5:c.7780+10A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001458.5(FLNC):​c.7780+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,599,408 control chromosomes in the GnomAD database, including 5 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.69
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-128857346-A-G is Benign according to our data. Variant chr7-128857346-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.7780+10A>G		intron	N/A	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.7681+10A>G		intron	N/A	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.103-3949T>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.7780+10A>G		intron	N/A	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.7681+10A>G		intron	N/A	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.7678+10A>G		intron	N/A	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 607 AN: 151938 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00281 AC: 685 AN: 243776 AF XY: 0.00240

Gnomad AFR exome AF: 0.00969

Gnomad AMR exome AF: 0.00624

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00213

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00184 AC: 2656 AN: 1447352 Hom.: 4 Cov.: 31 AF XY: 0.00170 AC XY: 1228 AN XY: 720652

African (AFR) AF: 0.0112 AC: 371 AN: 33254

American (AMR) AF: 0.00549 AC: 244 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00661 AC: 262 AN: 39650

South Asian (SAS) AF: 0.000732 AC: 63 AN: 86024

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 53018

Middle Eastern (MID) AF: 0.00313 AC: 15 AN: 4788

European-Non Finnish (NFE) AF: 0.00138 AC: 1518 AN: 1100328

Other (OTH) AF: 0.00201 AC: 120 AN: 59768

GnomAD4 genome AF: 0.00400 AC: 608 AN: 152056 Hom.: 1 Cov.: 33 AF XY: 0.00378 AC XY: 281 AN XY: 74342

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0102 AC: 422 AN: 41418

American (AMR) AF: 0.00308 AC: 47 AN: 15274

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

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 67954

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00249 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;na:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.45
PhyloP100		-4.7
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: rs201149834; hg19: chr7-128497400;