chr2-240630178-G-A

Position:

• chr2-240630178-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005301.5(GPR35):​c.226G>A​(p.Val76Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,590,726 control chromosomes in the GnomAD database, including 164 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 0.018 (79 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (85 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.96

Genes affected

GPR35 (HGNC:4492): (G protein-coupled receptor 35) Enables C-X-C chemokine receptor activity. Involved in several processes, including chemokine-mediated signaling pathway; negative regulation of voltage-gated calcium channel activity; and positive regulation of cytosolic calcium ion concentration. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022691786).
• BP6: Variant 2-240630178-G-A is Benign according to our data. Variant chr2-240630178-G-A is described in ClinVar as [Benign]. Clinvar id is 791899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.226G>A	p.Val76Met	missense_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.319G>A	p.Val107Met	missense_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.319G>A	p.Val107Met	missense_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.319G>A	p.Val107Met	missense_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.226G>A	p.Val76Met	missense_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2673 AN: 152138 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00564 AC: 1350 AN: 239472 Hom.: 38 AF XY: 0.00399 AC XY: 519 AN XY: 130158

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000243

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00222 AC: 3190 AN: 1438470 Hom.: 85 Cov.: 34 AF XY: 0.00191 AC XY: 1365 AN XY: 713444

Gnomad4 AFR exome AF: 0.0635

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000244

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.0176 AC: 2674 AN: 152256 Hom.: 79 Cov.: 33 AF XY: 0.0165 AC XY: 1225 AN XY: 74450

Gnomad4 AFR AF: 0.0597

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00553 Hom.: 13

Bravo AF: 0.0197

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00629 AC: 763

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.069
DANN	Benign	0.83
DEOGEN2	Benign	0.0084	T;T;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.61	.;.;T;.;T
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N;.;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.32	N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.35	T;T;D;T;.
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.32	B;B;.;B;B
Vest4		0.026
MVP		0.25
MPC		0.29
ClinPred		0.013	T
GERP RS		-8.0
Varity_R		0.037
gMVP		0.13

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: rs13387859; hg19: chr2-241569595;