rs61997249

Variant names:

• chr7-1057919-G-A
• rs61997249
• NM_001303473.2:c.404G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001303473.2(GPR146):​c.404G>A​(p.Arg135Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 774,898 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (11 hom.)
• Consequence: GPR146 NM_001303473.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.21
• Publications: 10 publications found

Genes affected

GPR146 (HGNC:21718): (G protein-coupled receptor 146) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CHLSN (HGNC:22421): (chromosome 7 open reading frame 50) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000257607 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013405383).
• BP6: Variant 7-1057919-G-A is Benign according to our data. Variant chr7-1057919-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2657177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303473.2. 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
	GPR146	NM_001303473.2	MANE Select	c.404G>A	p.Arg135Gln	missense	Exon 2 of 2	NP_001290402.1	Q96CH1
	CHLSN	NM_001318252.2	MANE Select	c.130-47776C>T		intron	N/A	NP_001305181.1	Q9BRJ6
	GPR146	NM_001303474.2		c.404G>A	p.Arg135Gln	missense	Exon 3 of 3	NP_001290403.1	Q96CH1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR146	ENST00000444847.2	TSL:2 MANE Select	c.404G>A	p.Arg135Gln	missense	Exon 2 of 2	ENSP00000410743.2	Q96CH1
	GPR146	ENST00000397095.2	TSL:1	c.404G>A	p.Arg135Gln	missense	Exon 2 of 2	ENSP00000380283.1	Q96CH1
	CHLSN	ENST00000397098.8	TSL:1 MANE Select	c.130-47776C>T		intron	N/A	ENSP00000380286.3	Q9BRJ6

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00171 AC: 422 AN: 246410 AF XY: 0.00215

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00184 AC: 1146 AN: 622552 Hom.: 11 Cov.: 0 AF XY: 0.00220 AC XY: 747 AN XY: 339782

African (AFR) AF: 0.000396 AC: 7 AN: 17690

American (AMR) AF: 0.000846 AC: 37 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.00334 AC: 70 AN: 20974

East Asian (EAS) AF: 0.0000555 AC: 2 AN: 36064

South Asian (SAS) AF: 0.00559 AC: 390 AN: 69796

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47078

Middle Eastern (MID) AF: 0.00627 AC: 26 AN: 4148

European-Non Finnish (NFE) AF: 0.00150 AC: 525 AN: 350026

Other (OTH) AF: 0.00266 AC: 88 AN: 33042

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74490

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68028

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00158 Hom.: 4

Bravo AF: 0.000948

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00170 AC: 206

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00231

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.34
Sift	Benign	0.045	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.53
MPC		0.46
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.30
gMVP		0.47
Mutation Taster		=74/26	polymorphism

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: rs61997249; hg19: chr7-1097555;