ENST00000522142.1:c.-292+71G>C

Variant names:

• chr8-38996522-C-G
• rs10105311
• ENST00000522142.1:c.-292+71G>C

Variant summary

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

The ENST00000522142.1(TM2D2):​c.-292+71G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,411,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TM2D2 ENST00000522142.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.589
• Publications: 0 publications found

Genes affected

TM2D2 (HGNC:24127): (TM2 domain containing 2) The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. This gene has multiple alternatively spliced transcript variants which encode two different isoforms. [provided by RefSeq, Jul 2008]

ADAM9 (HGNC:216): (ADAM metallopeptidase domain 9) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The protein encoded by this gene interacts with SH3 domain-containing proteins, binds mitotic arrest deficient 2 beta protein, and is also involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. Several alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jul 2010]

ADAM9 Gene-Disease associations (from GenCC):

• ADAM9-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 (BayesDel_noAF=-0.73).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000522142.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D2	NM_078473.3	MANE Select	c.-83G>C		upstream_gene	N/A	NP_510882.1
	TM2D2	NM_001024380.2		c.-395G>C		upstream_gene	N/A	NP_001019551.1
	TM2D2	NM_001024381.2		c.-294G>C		upstream_gene	N/A	NP_001019552.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D2	ENST00000522142.1	TSL:3	c.-292+71G>C		intron	N/A	ENSP00000428394.1
	TM2D2	ENST00000520152.1	TSL:4	c.-191+71G>C		intron	N/A	ENSP00000428203.1
	TM2D2	ENST00000456397.7	TSL:1 MANE Select	c.-83G>C		upstream_gene	N/A	ENSP00000416050.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000128 AC: 18 AN: 1411062 Hom.: 0 Cov.: 38 AF XY: 0.0000129 AC XY: 9 AN XY: 695610

African (AFR) AF: 0.00 AC: 0 AN: 32310

American (AMR) AF: 0.00 AC: 0 AN: 39026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23984

East Asian (EAS) AF: 0.00 AC: 0 AN: 38208

South Asian (SAS) AF: 0.00 AC: 0 AN: 81492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5170

European-Non Finnish (NFE) AF: 0.0000166 AC: 18 AN: 1082802

Other (OTH) AF: 0.00 AC: 0 AN: 58162

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		0.59
PromoterAI		-0.064	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10105311; hg19: chr8-38854041;