chr2-240630075-G-C

Position:

• chr2-240630075-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005301.5(GPR35):​c.123G>C​(p.Ala41Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,611,404 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (23 hom., cov: 33)
  • Exomes 𝑓: 0.015 (216 hom.)
• Consequence: GPR35 NM_005301.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.29

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-240630075-G-C is Benign according to our data. Variant chr2-240630075-G-C is described in ClinVar as [Benign]. Clinvar id is 790442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00939 (1430/152334) while in subpopulation NFE AF= 0.0159 (1083/68030). AF 95% confidence interval is 0.0151. There are 23 homozygotes in gnomad4. There are 618 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.123G>C	p.Ala41Ala	synonymous_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.216G>C	p.Ala72Ala	synonymous_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.216G>C	p.Ala72Ala	synonymous_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.216G>C	p.Ala72Ala	synonymous_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.123G>C	p.Ala41Ala	synonymous_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.00940 AC: 1431 AN: 152216 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00903 AC: 2248 AN: 248960 Hom.: 29 AF XY: 0.00914 AC XY: 1234 AN XY: 135024

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.0148 AC: 21622 AN: 1459070 Hom.: 216 Cov.: 33 AF XY: 0.0145 AC XY: 10517 AN XY: 725982

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00497

Gnomad4 FIN exome AF: 0.00573

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.00939 AC: 1430 AN: 152334 Hom.: 23 Cov.: 33 AF XY: 0.00830 AC XY: 618 AN XY: 74486

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00591 Hom.: 3

Bravo AF: 0.00964

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0153

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
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.14
DANN	Benign	0.75

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: rs61734451; hg19: chr2-241569492;