1-240092766-ACAGCAGCAGCAG-ACAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020066.5(FMN2):c.674_676dup(p.Gln225dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,609,674 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (18 hom.)
• Consequence: FMN2 NM_020066.5 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0480

Genes affected

FMN2 (HGNC:14074): (formin 2) This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-240092766-A-ACAG is Benign according to our data. Variant chr1-240092766-A-ACAG is described in ClinVar as [Benign]. Clinvar id is 435215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00936 (1424/152104) while in subpopulation AFR AF= 0.0321 (1333/41532). AF 95% confidence interval is 0.0307. There are 19 homozygotes in gnomad4. There are 692 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMN2	NM_020066.5	c.674_676dup	p.Gln225dup	inframe_insertion	1/18	ENST00000319653.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMN2	ENST00000319653.14	c.674_676dup	p.Gln225dup	inframe_insertion	1/18	5	NM_020066.5	P1
FMN2	ENST00000447095.5	c.-87+24710_-87+24712dup		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1412 AN: 151992 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00187 AC: 417 AN: 223544 Hom.: 3 AF XY: 0.00151 AC XY: 184 AN XY: 121756

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000595

Gnomad SAS exome AF: 0.0000701

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000720

GnomAD4 exome AF: 0.000820 AC: 1195 AN: 1457570 Hom.: 18 Cov.: 88 AF XY: 0.000716 AC XY: 519 AN XY: 724938

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00936 AC: 1424 AN: 152104 Hom.: 19 Cov.: 33 AF XY: 0.00930 AC XY: 692 AN XY: 74372

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00805

Bravo AF: 0.00992

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 30, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs532298569; hg19: chr1-240256066;