2-231108702-T-C

Variant names:

• chr2-231108702-T-C
• rs6736017
• NM_000867.5:c.1261A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000867.5(HTR2B):​c.1261A>G​(p.Met421Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,138 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (149 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (111 hom.)
• Consequence: HTR2B NM_000867.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0500
• Publications: 11 publications found

Genes affected

HTR2B (HGNC:5294): (5-hydroxytryptamine receptor 2B) This gene encodes one of the several different receptors for 5-hydroxytryptamine (serotonin) that belongs to the G-protein coupled receptor 1 family. Serotonin is a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. Serotonin receptors mediate many of the central and peripheral physiologic functions of serotonin, including regulation of cardiovascular functions and impulsive behavior. Population and family-based analyses of a minor allele (glutamine-to-stop substitution, designated Q20*) which blocks expression of this protein, and knockout studies in mice, suggest a role for this gene in impulsivity. However, other factors, such as elevated testosterone levels, may also be involved. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

PSMD1 (HGNC:9554): (proteasome 26S subunit, non-ATPase 1) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes the largest non-ATPase subunit of the 19S regulator lid, which is responsible for substrate recognition and binding. There is evidence that this proteasome and its subunits interact with viral proteins, including those of coronaviruses. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Aug 2020]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014075637).
• BP6: Variant 2-231108702-T-C is Benign according to our data. Variant chr2-231108702-T-C is described in ClinVar as Benign. ClinVar VariationId is 791235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000867.5. 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
	HTR2B	NM_000867.5	MANE Select	c.1261A>G	p.Met421Val	missense	Exon 4 of 4	NP_000858.3
	PSMD1	NM_002807.4	MANE Select	c.1883+21521T>C		intron	N/A	NP_002798.2
	HTR2B	NM_001320758.2		c.1135A>G	p.Met379Val	missense	Exon 4 of 4	NP_001307687.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2B	ENST00000258400.4	TSL:1 MANE Select	c.1261A>G	p.Met421Val	missense	Exon 4 of 4	ENSP00000258400.3	P41595
	PSMD1	ENST00000308696.11	TSL:1 MANE Select	c.1883+21521T>C		intron	N/A	ENSP00000309474.6	Q99460-1
	PSMD1	ENST00000431051.6	TSL:1	n.*1566+21521T>C		intron	N/A	ENSP00000400483.1	F8WCE3

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3631 AN: 152182 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00627 AC: 1576 AN: 251164 AF XY: 0.00430

Gnomad AFR exome AF: 0.0845

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00235 AC: 3441 AN: 1461838 Hom.: 111 Cov.: 32 AF XY: 0.00201 AC XY: 1463 AN XY: 727218

African (AFR) AF: 0.0817 AC: 2734 AN: 33476

American (AMR) AF: 0.00494 AC: 221 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111988

Other (OTH) AF: 0.00536 AC: 324 AN: 60392

GnomAD4 genome AF: 0.0239 AC: 3644 AN: 152300 Hom.: 149 Cov.: 32 AF XY: 0.0228 AC XY: 1698 AN XY: 74492

African (AFR) AF: 0.0838 AC: 3481 AN: 41542

American (AMR) AF: 0.00798 AC: 122 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00924 Hom.: 126

Bravo AF: 0.0265

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0844 AC: 372

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00776 AC: 942

Asia WGS AF: 0.00318 AC: 11 AN: 3476

EpiCase AF: 0.000491

EpiControl AF: 0.000356

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	0.059
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.6
DANN	Benign	0.71
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L
PhyloP100		0.050
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.085
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.096
MVP		0.59
MPC		0.15
ClinPred		0.0019	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.46
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6736017; hg19: chr2-231973416;