chr2-240630118-C-T

Position:

• chr2-240630118-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005301.5(GPR35):​c.166C>T​(p.Arg56Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,606,638 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (12 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.349

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=0.008017927).
• BP6: Variant 2-240630118-C-T is Benign according to our data. Variant chr2-240630118-C-T is described in ClinVar as [Benign]. Clinvar id is 780371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00504 (768/152320) while in subpopulation AFR AF= 0.0168 (697/41568). AF 95% confidence interval is 0.0157. There are 4 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.166C>T	p.Arg56Cys	missense_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.259C>T	p.Arg87Cys	missense_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.259C>T	p.Arg87Cys	missense_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.259C>T	p.Arg87Cys	missense_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.166C>T	p.Arg56Cys	missense_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 769 AN: 152202 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00173 AC: 425 AN: 245544 Hom.: 7 AF XY: 0.00121 AC XY: 161 AN XY: 133408

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000775 AC: 1127 AN: 1454318 Hom.: 12 Cov.: 33 AF XY: 0.000709 AC XY: 513 AN XY: 723756

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00639

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00504 AC: 768 AN: 152320 Hom.: 4 Cov.: 33 AF XY: 0.00455 AC XY: 339 AN XY: 74486

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00168 Hom.: 3

Bravo AF: 0.00568

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0163 AC: 72

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00198 AC: 241

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T;T;.;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.83	.;.;T;.;T
MetaRNN	Benign	0.0080	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;M;.;M;M
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.3	D;D;.;D;.
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;.;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.42
MVP		0.45
MPC		1.1
ClinPred		0.053	T
GERP RS		3.1
Varity_R		0.61
gMVP		0.23

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: rs115880579; hg19: chr2-241569535;