1-240092766-ACAGCAGCAGCAG-ACAGCAGCAGCAGCAG

Variant names:

• chr1-240092766-A-ACAG
• rs532298569
• NM_020066.5:c.674_676dupAGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The ENST00000319653.14(FMN2):​c.674_676dupAGC​(p.Gln225dup) variant causes a disruptive 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 ENST00000319653.14 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0480
• Publications: 1 publications found

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]

FMN2 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 47

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000319653.14
• BP6: Variant 1-240092766-A-ACAG is Benign according to our data. Variant chr1-240092766-A-ACAG is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000319653.14. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	NM_020066.5	MANE Select	c.674_676dupAGC	p.Gln225dup	disruptive_inframe_insertion	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.674_676dupAGC	p.Gln225dup	disruptive_inframe_insertion	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.674_676dupAGC	p.Gln225dup	disruptive_inframe_insertion	Exon 1 of 15	NP_001335023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.674_676dupAGC	p.Gln225dup	disruptive_inframe_insertion	Exon 1 of 18	ENSP00000318884.9
	FMN2	ENST00000447095.5	TSL:3	c.-87+24710_-87+24712dupAGC		intron	N/A	ENSP00000409308.1

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

GnomAD2 exomes AF: 0.00187 AC: 417 AN: 223544 AF XY: 0.00151

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 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

African (AFR) AF: 0.0275 AC: 917 AN: 33392

American (AMR) AF: 0.00179 AC: 79 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39626

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52230

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5692

European-Non Finnish (NFE) AF: 0.0000702 AC: 78 AN: 1110382

Other (OTH) AF: 0.00176 AC: 106 AN: 60180

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

African (AFR) AF: 0.0321 AC: 1333 AN: 41532

American (AMR) AF: 0.00412 AC: 63 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67924

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.00992

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.048
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs532298569; hg19: chr1-240256066; COSMIC: COSV60461630;