1-240092268-GGGC-G

Variant names:

• chr1-240092268-GGGC-G
• rs71929261
• NM_020066.5:c.174_176delCGG

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_020066.5(FMN2):​c.174_176delCGG​(p.Gly59del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,415,582 control chromosomes in the GnomAD database, including 415,921 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.77 (44723 hom., cov: 0)
  • Exomes 𝑓: 0.76 (415921 hom.)
  • Failed GnomAD Quality Control
• Consequence: FMN2 NM_020066.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020066.5
• BP6: Variant 1-240092268-GGGC-G is Benign according to our data. Variant chr1-240092268-GGGC-G is described in ClinVar as Benign. ClinVar VariationId is 1285272.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020066.5. 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
	FMN2	NM_020066.5	MANE Select	c.174_176delCGG	p.Gly59del	disruptive_inframe_deletion	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.174_176delCGG	p.Gly59del	disruptive_inframe_deletion	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.174_176delCGG	p.Gly59del	disruptive_inframe_deletion	Exon 1 of 15	NP_001335023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.174_176delCGG	p.Gly59del	disruptive_inframe_deletion	Exon 1 of 18	ENSP00000318884.9	Q9NZ56-1
	FMN2	ENST00000447095.5	TSL:3	c.-87+24210_-87+24212delCGG		intron	N/A	ENSP00000409308.1	B0QZA8

Frequencies

GnomAD3 genomes AF: 0.770 AC: 115118 AN: 149410 Hom.: 44653 Cov.: 0

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.762

GnomAD2 exomes AF: 0.748 AC: 131017 AN: 175182 AF XY: 0.748

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.791

Gnomad ASJ exome AF: 0.768

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.769

GnomAD4 exome AF: 0.764 AC: 1081365 AN: 1415582 Hom.: 415921 AF XY: 0.763 AC XY: 533724 AN XY: 699880

African (AFR) AF: 0.780 AC: 25500 AN: 32696

American (AMR) AF: 0.782 AC: 30472 AN: 38966

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 18906 AN: 24854

East Asian (EAS) AF: 0.466 AC: 17903 AN: 38378

South Asian (SAS) AF: 0.744 AC: 59846 AN: 80486

European-Finnish (FIN) AF: 0.830 AC: 39773 AN: 47944

Middle Eastern (MID) AF: 0.749 AC: 3775 AN: 5042

European-Non Finnish (NFE) AF: 0.772 AC: 840937 AN: 1088710

Other (OTH) AF: 0.756 AC: 44253 AN: 58506

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.771 AC: 115256 AN: 149522 Hom.: 44723 Cov.: 0 AF XY: 0.771 AC XY: 56162 AN XY: 72850

African (AFR) AF: 0.789 AC: 32068 AN: 40640

American (AMR) AF: 0.771 AC: 11649 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2611 AN: 3436

East Asian (EAS) AF: 0.455 AC: 2250 AN: 4950

South Asian (SAS) AF: 0.750 AC: 3530 AN: 4708

European-Finnish (FIN) AF: 0.830 AC: 8419 AN: 10144

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.777 AC: 52269 AN: 67274

Other (OTH) AF: 0.763 AC: 1584 AN: 2076

Alfa AF: 0.743 Hom.: 4337

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal recessive 47 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=75/25	polymorphism (auto)

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: rs71929261; hg19: chr1-240255568; COSMIC: COSV60415736;