14-105644577-G-T

Variant names:

• chr14-105644577-G-T
• rs11627594
• ENST00000641095.1:c.214C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000641095.1(IGHG2):​c.214C>A​(p.Pro72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 774,208 control chromosomes in the GnomAD database, including 66,816 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (10321 hom., cov: 33)
  • Exomes 𝑓: 0.41 (56495 hom.)
• Consequence: IGHG2 ENST00000641095.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.160
• Publications: 10 publications found

Genes affected

IGHG2 (HGNC:5526): (immunoglobulin heavy constant gamma 2 (G2m marker)) Predicted to enable antigen binding activity and immunoglobulin receptor binding activity. Predicted to be involved in several processes, including activation of immune response; defense response to other organism; and phagocytosis. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

IGHG2 Gene-Disease associations (from GenCC):

• recurrent infections associated with rare immunoglobulin isotypes deficiency

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

IGH (HGNC:5477):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHG2	unassigned_transcript_2471	c.211C>A	p.Pro71Thr	missense_variant	Exon 1 of 4
IGH		n.105644577G>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHG2	ENST00000641095.1	c.214C>A	p.Pro72Thr	missense_variant	Exon 1 of 6			ENSP00000493129.1
IGHG2	ENST00000390545.3	c.214C>A	p.Pro72Thr	missense_variant	Exon 1 of 4	6		ENSP00000374987.2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 49734 AN: 148816 Hom.: 10319 Cov.: 33

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.395 AC: 97037 AN: 245892 AF XY: 0.408

Gnomad AFR exome AF: 0.0758

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.605

Gnomad EAS exome AF: 0.536

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.407 AC: 254466 AN: 625270 Hom.: 56495 Cov.: 0 AF XY: 0.413 AC XY: 140865 AN XY: 340702

African (AFR) AF: 0.0790 AC: 1391 AN: 17618

American (AMR) AF: 0.222 AC: 9687 AN: 43672

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 12341 AN: 20902

East Asian (EAS) AF: 0.266 AC: 9575 AN: 36038

South Asian (SAS) AF: 0.376 AC: 26175 AN: 69528

European-Finnish (FIN) AF: 0.415 AC: 22023 AN: 53036

Middle Eastern (MID) AF: 0.531 AC: 1335 AN: 2514

European-Non Finnish (NFE) AF: 0.452 AC: 157925 AN: 349116

Other (OTH) AF: 0.427 AC: 14014 AN: 32846

GnomAD4 genome AF: 0.334 AC: 49721 AN: 148938 Hom.: 10321 Cov.: 33 AF XY: 0.332 AC XY: 24153 AN XY: 72666

African (AFR) AF: 0.0843 AC: 3400 AN: 40352

American (AMR) AF: 0.288 AC: 4320 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2049 AN: 3392

East Asian (EAS) AF: 0.485 AC: 2424 AN: 5000

South Asian (SAS) AF: 0.380 AC: 1783 AN: 4688

European-Finnish (FIN) AF: 0.414 AC: 4297 AN: 10382

Middle Eastern (MID) AF: 0.500 AC: 145 AN: 290

European-Non Finnish (NFE) AF: 0.450 AC: 30103 AN: 66918

Other (OTH) AF: 0.374 AC: 762 AN: 2038

Alfa AF: 0.401 Hom.: 3841

Bravo AF: 0.314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		-0.16

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: rs11627594; hg19: chr14-106110914; COSMIC: COSV66640485;