chr14-105643800-C-T

Variant names:

• chr14-105643800-C-T
• rs8009156
• ENST00000641095.1:c.481G>A

Variant summary

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

The ENST00000641095.1(IGHG2):​c.481G>A​(p.Val161Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 779,382 control chromosomes in the GnomAD database, including 68,607 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 (10781 hom., cov: 34)
  • Exomes 𝑓: 0.41 (57826 hom.)
• Consequence: IGHG2 ENST00000641095.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.01
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHG2	unassigned_transcript_2471	c.478G>A	p.Val160Met	missense_variant	Exon 3 of 4
IGH		n.105643800C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHG2	ENST00000641095.1	c.481G>A	p.Val161Met	missense_variant	Exon 3 of 6			ENSP00000493129.1
IGHG2	ENST00000390545.3	c.481G>A	p.Val161Met	missense_variant	Exon 3 of 4	6		ENSP00000374987.2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50615 AN: 151422 Hom.: 10779 Cov.: 34

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.371

GnomAD2 exomes AF: 0.394 AC: 97225 AN: 246622 AF XY: 0.408

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.604

Gnomad EAS exome AF: 0.536

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.409 AC: 256701 AN: 627842 Hom.: 57826 Cov.: 0 AF XY: 0.415 AC XY: 142090 AN XY: 342024

African (AFR) AF: 0.0788 AC: 1392 AN: 17674

American (AMR) AF: 0.223 AC: 9739 AN: 43708

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 12502 AN: 20976

East Asian (EAS) AF: 0.266 AC: 9578 AN: 36040

South Asian (SAS) AF: 0.380 AC: 26477 AN: 69708

European-Finnish (FIN) AF: 0.417 AC: 22144 AN: 53106

Middle Eastern (MID) AF: 0.512 AC: 2015 AN: 3932

European-Non Finnish (NFE) AF: 0.454 AC: 158736 AN: 349672

Other (OTH) AF: 0.427 AC: 14118 AN: 33026

GnomAD4 genome AF: 0.334 AC: 50600 AN: 151540 Hom.: 10781 Cov.: 34 AF XY: 0.333 AC XY: 24633 AN XY: 74038

African (AFR) AF: 0.0826 AC: 3420 AN: 41412

American (AMR) AF: 0.288 AC: 4385 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2111 AN: 3464

East Asian (EAS) AF: 0.482 AC: 2484 AN: 5152

South Asian (SAS) AF: 0.381 AC: 1815 AN: 4770

European-Finnish (FIN) AF: 0.418 AC: 4403 AN: 10522

Middle Eastern (MID) AF: 0.503 AC: 146 AN: 290

European-Non Finnish (NFE) AF: 0.452 AC: 30601 AN: 67724

Other (OTH) AF: 0.377 AC: 791 AN: 2098

Alfa AF: 0.408 Hom.: 6073

Bravo AF: 0.314

Asia WGS AF: 0.437 AC: 1518 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.20
DANN	Benign	0.97
PhyloP100		-3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8009156; hg19: chr14-106110137; COSMIC: COSV66640482;