2-219221256-T-G

Position:

• chr2-219221256-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001077198.3(ATG9A):​c.2192A>C​(p.His731Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATG9A NM_001077198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.40

Genes affected

ATG9A (HGNC:22408): (autophagy related 9A) Acts upstream of or within autophagosome assembly. Located in endosome; phagophore assembly site; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000284820 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG9A	NM_001077198.3	c.2192A>C	p.His731Pro	missense_variant	14/16	ENST00000361242.9	NP_001070666.1
ATG9A	NM_024085.5	c.2192A>C	p.His731Pro	missense_variant	13/15		NP_076990.4
ATG9A	NR_104255.2	n.2316A>C		non_coding_transcript_exon_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG9A	ENST00000361242.9	c.2192A>C	p.His731Pro	missense_variant	14/16	2	NM_001077198.3	ENSP00000355173.4
ENSG00000284820	ENST00000446716.5	n.437A>C		non_coding_transcript_exon_variant	4/22	2		ENSP00000398528.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The c.2192A>C (p.H731P) alteration is located in exon 14 (coding exon 12) of the ATG9A gene. This alteration results from a A to C substitution at nucleotide position 2192, causing the histidine (H) at amino acid position 731 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.068	T;T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	2.0	M;M;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.99	D;D;D;.
Vest4		0.77
MutPred		0.20		Gain of loop (P = 0.024);Gain of loop (P = 0.024);Gain of loop (P = 0.024);.;
MVP		0.58
MPC		0.84
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.36
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220085978;