chr21-46490692-G-T

Variant names:

• chr21-46490692-G-T
• rs781249841
• NM_015151.4:c.256G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015151.4(DIP2A):​c.256G>T​(p.Ala86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A86T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DIP2A NM_015151.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.16
• Publications: 2 publications found

Genes affected

DIP2A (HGNC:17217): (disco interacting protein 2 homolog A) The protein encoded by this gene may be involved in axon patterning in the central nervous system. This gene is not highly expressed. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

DIP2A Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030153185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015151.4. 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
	DIP2A	NM_015151.4	MANE Select	c.256G>T	p.Ala86Ser	missense	Exon 3 of 38	NP_055966.2
	DIP2A	NM_001410751.1		c.256G>T	p.Ala86Ser	missense	Exon 3 of 39	NP_001397680.1	A0A494C143
	DIP2A	NM_001353942.2		c.256G>T	p.Ala86Ser	missense	Exon 3 of 38	NP_001340871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIP2A	ENST00000417564.3	TSL:1 MANE Select	c.256G>T	p.Ala86Ser	missense	Exon 3 of 38	ENSP00000392066.2	Q14689-1
	DIP2A	ENST00000457905.7	TSL:1	c.256G>T	p.Ala86Ser	missense	Exon 3 of 22	ENSP00000393434.3	Q14689-4
	DIP2A	ENST00000466639.5	TSL:1	c.256G>T	p.Ala86Ser	missense	Exon 3 of 20	ENSP00000430249.1	Q14689-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433626 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 2 AN XY: 710382

African (AFR) AF: 0.00 AC: 0 AN: 32972

American (AMR) AF: 0.00 AC: 0 AN: 40062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38298

South Asian (SAS) AF: 0.00 AC: 0 AN: 81868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098216

Other (OTH) AF: 0.00 AC: 0 AN: 59384

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.8
DANN	Benign	0.79
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		3.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.067
Sift	Benign	0.52	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.23		Gain of phosphorylation at A86 (P = 0.0013)
MVP		0.18
MPC		0.25
ClinPred		0.053	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.024
gMVP		0.10
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs781249841; hg19: chr21-47910605;