8-38996522-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000522142.1(TM2D2):​c.-292+71G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,562,718 control chromosomes in the GnomAD database, including 101,405 homozygotes. 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: 𝑓 0.31 (7361 hom., cov: 32)
  • Exomes 𝑓: 0.36 (94044 hom.)
• Consequence: TM2D2 ENST00000522142.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.589
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

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>A		upstream_gene	N/A	NP_510882.1
	TM2D2	NM_001024380.2		c.-395G>A		upstream_gene	N/A	NP_001019551.1
	TM2D2	NM_001024381.2		c.-294G>A		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>A		intron	N/A	ENSP00000428394.1
	TM2D2	ENST00000520152.1	TSL:4	c.-191+71G>A		intron	N/A	ENSP00000428203.1
	TM2D2	ENST00000456397.7	TSL:1 MANE Select	c.-83G>A		upstream_gene	N/A	ENSP00000416050.2

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46397 AN: 152044 Hom.: 7366 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.363 AC: 512167 AN: 1410554 Hom.: 94044 Cov.: 38 AF XY: 0.363 AC XY: 252258 AN XY: 695324

African (AFR) AF: 0.194 AC: 6280 AN: 32298

American (AMR) AF: 0.345 AC: 13432 AN: 38958

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 7772 AN: 23976

East Asian (EAS) AF: 0.226 AC: 8646 AN: 38190

South Asian (SAS) AF: 0.349 AC: 28410 AN: 81408

European-Finnish (FIN) AF: 0.360 AC: 17931 AN: 49876

Middle Eastern (MID) AF: 0.324 AC: 1673 AN: 5168

European-Non Finnish (NFE) AF: 0.377 AC: 407836 AN: 1082532

Other (OTH) AF: 0.347 AC: 20187 AN: 58148

GnomAD4 genome AF: 0.305 AC: 46413 AN: 152164 Hom.: 7361 Cov.: 32 AF XY: 0.304 AC XY: 22638 AN XY: 74378

African (AFR) AF: 0.205 AC: 8530 AN: 41540

American (AMR) AF: 0.312 AC: 4781 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1094 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1052 AN: 5170

South Asian (SAS) AF: 0.337 AC: 1625 AN: 4820

European-Finnish (FIN) AF: 0.356 AC: 3765 AN: 10582

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24522 AN: 67962

Other (OTH) AF: 0.298 AC: 631 AN: 2114

Alfa AF: 0.343 Hom.: 27929

Bravo AF: 0.296

Asia WGS AF: 0.275 AC: 955 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		0.59
PromoterAI		-0.34	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;