4-123090584-T-C

Variant names:

• chr4-123090584-T-C
• rs199626476
• NM_145207.3:c.2219T>C
• AFG2A p.Leu740Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). BP4BP6

The NM_145207.3(AFG2A):c.2219T>C (p.Leu740Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000133 (AC=215) in the gnomAD database across 1,613,972 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00404. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.61
• Publications: 3 publications found

Genes affected

AFG2A (HGNC:18119): (AAA ATPase AFG2A) 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_145207.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AFG2A NM_145207.3	MANE Select	c.2219T>C p.Leu740Ser	missense	Exon 14 of 16	Prot: NP_660208.2 UniProt:
	AFG2A NM_001438322.1		c.2291T>C p.Leu764Ser	missense	Exon 15 of 17	Prot: NP_001425251.1
	AFG2A NM_001437913.1		c.2288T>C p.Leu763Ser	missense	Exon 15 of 17	Prot: NP_001424842.1 UniProt:

AFG2A NM_145207.3

MANE Select

HGVSc / HGVSpc.2219T>Cp.Leu740Ser

Exon rankExon 14 of 16

missense

Prot: NP_660208.2UniProt: Q8NB90-1

AFG2A NM_001438322.1

HGVSc / HGVSpc.2291T>Cp.Leu764Ser

Exon rankExon 15 of 17

missense

Prot: NP_001425251.1

AFG2A NM_001437913.1

HGVSc / HGVSpc.2288T>Cp.Leu763Ser

Exon rankExon 15 of 17

missense

Prot: NP_001424842.1UniProt: A0A6Q8PGU6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AFG2A ENST00000274008.5	TSL:1MANE Select	c.2219T>C p.Leu740Ser	missense	Exon 14 of 16	Prot: ENSP00000274008.3 UniProt:
	AFG2A ENST00000422835.2	TSL:1	n.2261T>C	non_coding_transcript_exon	Exon 14 of 15	Prot:
	AFG2A ENST00000675612.1		c.2288T>C p.Leu763Ser	missense	Exon 15 of 17	Prot: ENSP00000502453.1 UniProt:

AFG2A ENST00000274008.5

TSL:1MANE Select

HGVSc / HGVSpc.2219T>Cp.Leu740Ser

Exon rankExon 14 of 16

missense

Prot: ENSP00000274008.3UniProt: Q8NB90-1

AFG2A ENST00000422835.2

TSL:1

HGVSc / HGVSpn.2261T>C

Exon rankExon 14 of 15

non_coding_transcript_exon

Prot:

AFG2A ENST00000675612.1

HGVSc / HGVSpc.2288T>Cp.Leu763Ser

Exon rankExon 15 of 17

missense

Prot: ENSP00000502453.1UniProt: A0A6Q8PGU6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000237	AC:36	Hom:0	AN:152198	Cov:33
GnomAD2 exomes	AF: 0.000159	AC:40	Hom:	AN:251308	Cov:
GnomAD4 exome	AF: 0.000121	AC:177	Hom:0	AN:1461656	Cov:30
GnomAD4 genome	AF: 0.000249	AC:38	Hom:0	AN:152316	Cov:33
TOPMed (Bravo)	AF: 0.000325	AC:86	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000273	AC:50	Hom:1	AN:182884	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000384	AC:5	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.000866	AC:3	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.0124	AC:25	Hom:	AN:2010	Cov:
Turkish Variome	AF: 0.000298	AC:2	Hom:0	AN:6720	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28396	0.0000347	1	28812
Epi25(Epilepsy)	0.000143	6	41888	0.000135	9	66870
SCHEMA(Schizophrenia)	0.00310	351	113178	0.00292	557	190644

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.53
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.15	N
FuncVEP CTI	Benign	0.00018
GPN-Star LLR	N/A	-1.3
GPN-Star score	N/A	1.3
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.63	T
Mutation Taster	N/A	93/7	polymorphism
PhyloP100	Benign	2.6
popEVE	Benign	-2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Varity_R	N/A	0.033
VESM-3B	Benign	-2.3

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs199626476;

hg19: chr4-124011739;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar