19-3119367-G-C

Variant names:

• chr19-3119367-G-C
• rs73527836
• NM_002067.5:c.889+8G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002067.5(GNA11):​c.889+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,612,486 control chromosomes in the GnomAD database, including 1,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (397 hom., cov: 32)
  • Exomes 𝑓: 0.016 (685 hom.)
• Consequence: GNA11 NM_002067.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001836
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.62
• Publications: 3 publications found

Genes affected

GNA11 (HGNC:4379): (G protein subunit alpha 11) The protein encoded by this gene belongs to the family of guanine nucleotide-binding proteins (G proteins), which function as modulators or transducers in various transmembrane signaling systems. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes one of the alpha subunits (subunit alpha-11). Mutations in this gene have been associated with hypocalciuric hypercalcemia type II (HHC2) and hypocalcemia dominant 2 (HYPOC2). Patients with HHC2 and HYPOC2 exhibit decreased or increased sensitivity, respectively, to changes in extracellular calcium concentrations. [provided by RefSeq, Dec 2013]

GNA11 Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• congenital hemangioma

  Inheritance: AD Classification: STRONG Submitted by: G2P
• familial hypocalciuric hypercalcemia 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267139 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-3119367-G-C is Benign according to our data. Variant chr19-3119367-G-C is described in ClinVar as Benign. ClinVar VariationId is 258549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNA11	NM_002067.5	c.889+8G>C		splice_region_variant, intron_variant	Intron 6 of 6	ENST00000078429.9	NP_002058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNA11	ENST00000078429.9	c.889+8G>C		splice_region_variant, intron_variant	Intron 6 of 6	1	NM_002067.5	ENSP00000078429.3

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7452 AN: 151954 Hom.: 398 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0471

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0270 AC: 6747 AN: 249494 AF XY: 0.0264

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0276

GnomAD4 exome AF: 0.0163 AC: 23757 AN: 1460414 Hom.: 685 Cov.: 35 AF XY: 0.0172 AC XY: 12461 AN XY: 726480

African (AFR) AF: 0.151 AC: 5049 AN: 33452

American (AMR) AF: 0.0184 AC: 821 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 622 AN: 26048

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0514 AC: 4427 AN: 86180

European-Finnish (FIN) AF: 0.0268 AC: 1422 AN: 52996

Middle Eastern (MID) AF: 0.0595 AC: 343 AN: 5762

European-Non Finnish (NFE) AF: 0.00862 AC: 9577 AN: 1111270

Other (OTH) AF: 0.0247 AC: 1492 AN: 60322

GnomAD4 genome AF: 0.0491 AC: 7463 AN: 152072 Hom.: 397 Cov.: 32 AF XY: 0.0496 AC XY: 3685 AN XY: 74344

African (AFR) AF: 0.138 AC: 5697 AN: 41422

American (AMR) AF: 0.0234 AC: 358 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0470 AC: 226 AN: 4812

European-Finnish (FIN) AF: 0.0285 AC: 302 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 68008

Other (OTH) AF: 0.0436 AC: 92 AN: 2108

Alfa AF: 0.0115 Hom.: 10

Bravo AF: 0.0528

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Oct 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.54
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs73527836; hg19: chr19-3119365; COSMIC: COSV50038616; COSMIC: COSV50038616;