chr14-96289757-T-C

Variant names:

• chr14-96289757-T-C
• rs35258365
• NM_018036.7:c.5905A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018036.7(ATG2B):​c.5905A>G​(p.Ile1969Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,614,080 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (18 hom.)
• Consequence: ATG2B NM_018036.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22
• Publications: 3 publications found

Genes affected

ATG2B (HGNC:20187): (autophagy related 2B) This gene encodes a protein required for autophagy. The encoded protein is involved in autophagosome formation. A germline duplication of a region that includes this gene is associated with predisposition to myeloid malignancies. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023164153).
• BP6: Variant 14-96289757-T-C is Benign according to our data. Variant chr14-96289757-T-C is described in ClinVar as Benign. ClinVar VariationId is 735075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00656 (999/152226) while in subpopulation AFR AF = 0.0229 (950/41530). AF 95% confidence interval is 0.0217. There are 13 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018036.7. 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
	ATG2B	NM_018036.7	MANE Select	c.5905A>G	p.Ile1969Val	missense	Exon 41 of 42	NP_060506.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG2B	ENST00000359933.6	TSL:5 MANE Select	c.5905A>G	p.Ile1969Val	missense	Exon 41 of 42	ENSP00000353010.4	Q96BY7
	ATG2B	ENST00000938845.1		c.5869A>G	p.Ile1957Val	missense	Exon 41 of 42	ENSP00000608904.1
	ATG2B	ENST00000555263.1	TSL:2	n.191A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1001 AN: 152108 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00175 AC: 440 AN: 251472 AF XY: 0.00127

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000742 AC: 1084 AN: 1461854 Hom.: 18 Cov.: 30 AF XY: 0.000672 AC XY: 489 AN XY: 727236

African (AFR) AF: 0.0237 AC: 795 AN: 33480

American (AMR) AF: 0.00154 AC: 69 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1111982

Other (OTH) AF: 0.00136 AC: 82 AN: 60396

GnomAD4 genome AF: 0.00656 AC: 999 AN: 152226 Hom.: 13 Cov.: 33 AF XY: 0.00622 AC XY: 463 AN XY: 74420

African (AFR) AF: 0.0229 AC: 950 AN: 41530

American (AMR) AF: 0.00196 AC: 30 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00260 Hom.: 14

Bravo AF: 0.00735

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00216 AC: 262

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.9
DANN	Benign	0.49
DEOGEN2	Benign	0.00064	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.51	N
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.064
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.28
MPC		0.38
ClinPred		0.0080	T
GERP RS		2.9
Varity_R		0.014
gMVP		0.27
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs35258365; hg19: chr14-96756094;