Genetic Variant NM_006420.3:c.2276+6C>G (chr20-48985619-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_006420.3(ARFGEF2):c.2276+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ARFGEF2
NM_006420.3 splice_region, intron

Scores

Splicing: ADA: 0.00008010

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.564

Publications

0 publications found

Variant links:

Genes affected

ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

ARFGEF2 Gene-Disease associations (from GenCC):

periventricular heterotopia with microcephaly, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARFGEF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000479 (7/1461596) while in subpopulation EAS AF = 0.000176 (7/39698). AF 95% confidence interval is 0.000082. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 link	c.2276+6C>G	splice_region_variant, intron_variant	Intron 16 of 38	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_001410846.1 link	c.2273+6C>G	splice_region_variant, intron_variant	Intron 16 of 38		NP_001397775.1
ARFGEF2	XM_047439832.1 link	c.1712+6C>G	splice_region_variant, intron_variant	Intron 14 of 36		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 link	c.2276+6C>G		splice_region_variant, intron_variant	Intron 16 of 38	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250690

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000176

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.2

(source)

DANN

Benign

0.41

PhyloP100

-0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000080

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over