rs2201997

Variant names:

• chr4-123258087-G-T
• rs2201997
• NM_145207.3:c.2505+1907G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145207.3(AFG2A):​c.2505+1907G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 152,078 control chromosomes in the GnomAD database, including 45,586 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.77 (45586 hom., cov: 32)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 1 publications found

Genes affected

AFG2A (HGNC:18119): (AFG2 AAA ATPase homolog A) This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

AFG2A Gene-Disease associations (from GenCC):

• microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145207.3. 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
	AFG2A	NM_145207.3	MANE Select	c.2505+1907G>T		intron	N/A	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.2577+1907G>T		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.2574+1907G>T		intron	N/A	NP_001424842.1	A0A6Q8PGU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.2505+1907G>T		intron	N/A	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000675612.1		c.2574+1907G>T		intron	N/A	ENSP00000502453.1	A0A6Q8PGU6
	AFG2A	ENST00000905945.1		c.2502+1907G>T		intron	N/A	ENSP00000576004.1

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116421 AN: 151960 Hom.: 45554 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.773

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.766 AC: 116503 AN: 152078 Hom.: 45586 Cov.: 32 AF XY: 0.762 AC XY: 56676 AN XY: 74346

African (AFR) AF: 0.632 AC: 26179 AN: 41434

American (AMR) AF: 0.800 AC: 12222 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2548 AN: 3468

East Asian (EAS) AF: 0.550 AC: 2843 AN: 5166

South Asian (SAS) AF: 0.569 AC: 2729 AN: 4800

European-Finnish (FIN) AF: 0.915 AC: 9711 AN: 10608

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.847 AC: 57632 AN: 68006

Other (OTH) AF: 0.773 AC: 1630 AN: 2110

Alfa AF: 0.805 Hom.: 19599

Bravo AF: 0.757

Asia WGS AF: 0.648 AC: 2252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.70
PhyloP100		-0.042
Mutation Taster		=100/0	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: rs2201997; hg19: chr4-124179242;