chr19-3110201-C-T

Variant names:

• chr19-3110201-C-T
• rs61731116
• NM_002067.5:c.189C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002067.5(GNA11):​c.189C>T​(p.His63His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,613,544 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (39 hom.)
• Consequence: GNA11 NM_002067.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.131
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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), Orphanet, Genomics England PanelApp, Ambry Genetics
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 19-3110201-C-T is Benign according to our data. Variant chr19-3110201-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.131 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00174 (265/152198) while in subpopulation SAS AF = 0.0217 (105/4828). AF 95% confidence interval is 0.0184. There are 2 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 265 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002067.5. 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
	GNA11	NM_002067.5	MANE Select	c.189C>T	p.His63His	synonymous	Exon 2 of 7	NP_002058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNA11	ENST00000078429.9	TSL:1 MANE Select	c.189C>T	p.His63His	synonymous	Exon 2 of 7	ENSP00000078429.3
	GNA11	ENST00000586763.1	TSL:3	n.140-3129C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152080 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00304 AC: 759 AN: 249742 AF XY: 0.00396

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00280 AC: 4088 AN: 1461346 Hom.: 39 Cov.: 32 AF XY: 0.00328 AC XY: 2382 AN XY: 726980

African (AFR) AF: 0.000359 AC: 12 AN: 33468

American (AMR) AF: 0.000314 AC: 14 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26114

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39686

South Asian (SAS) AF: 0.0187 AC: 1610 AN: 86206

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53318

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5758

European-Non Finnish (NFE) AF: 0.00199 AC: 2210 AN: 1111784

Other (OTH) AF: 0.00333 AC: 201 AN: 60364

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152198 Hom.: 2 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74416

African (AFR) AF: 0.000289 AC: 12 AN: 41544

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.0217 AC: 105 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.00122

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00137

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs61731116; hg19: chr19-3110199; COSMIC: COSV109408523; COSMIC: COSV109408523;