chr2-231108702-T-C

Position:

• chr2-231108702-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2B	NM_000867.5	c.1261A>G	p.Met421Val	missense_variant	4/4	ENST00000258400.4	NP_000858.3
PSMD1	NM_002807.4	c.1883+21521T>C		intron_variant		ENST00000308696.11	NP_002798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2B	ENST00000258400.4	c.1261A>G	p.Met421Val	missense_variant	4/4	1	NM_000867.5	ENSP00000258400	P1
PSMD1	ENST00000308696.11	c.1883+21521T>C		intron_variant		1	NM_002807.4	ENSP00000309474	P1

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

GnomAD3 exomes AF: 0.00627 AC: 1576 AN: 251164 Hom.: 48 AF XY: 0.00430 AC XY: 584 AN XY: 135738

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.0817

Gnomad4 AMR exome AF: 0.00494

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00536

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

Gnomad4 AFR AF: 0.0838

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00448 Hom.: 48

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.98	N;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs6736017; hg19: chr2-231973416;