rs232230

Variant names:

• chr2-88857435-C-G
• rs232230
• ENST00000390237.2:c.247G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The ENST00000390237.2(IGKC):​c.247G>C​(p.Val83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 776,726 control chromosomes in the GnomAD database, including 9,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (3140 hom., cov: 32)
  • Exomes 𝑓: 0.11 (6026 hom.)
• Consequence: IGKC ENST00000390237.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.95
• Publications: 8 publications found

Genes affected

IGKC (HGNC:5716): (immunoglobulin kappa constant) Predicted to enable antigen binding activity and immunoglobulin receptor binding activity. Involved in retina homeostasis. Located in blood microparticle and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

IGKC Gene-Disease associations (from GenCC):

• recurrent infections associated with rare immunoglobulin isotypes deficiency

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

IGK (HGNC:5715):

ENSG00000240040 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to recurrent infections associated with rare immunoglobulin isotypes deficiency.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000390237.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGKC	ENST00000390237.2	TSL:6	c.247G>C	p.Val83Leu	missense	Exon 1 of 1	ENSP00000374777.2
	ENSG00000240040	ENST00000624935.3	TSL:2	n.39+4090G>C		intron	N/A
	ENSG00000295771	ENST00000732667.1		n.*143C>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25073 AN: 148942 Hom.: 3130 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.0669

Gnomad MID AF: 0.0984

Gnomad NFE AF: 0.0829

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.135 AC: 33280 AN: 245870 AF XY: 0.123

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.0370

Gnomad EAS exome AF: 0.308

Gnomad FIN exome AF: 0.0670

Gnomad NFE exome AF: 0.0811

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.111 AC: 69525 AN: 627700 Hom.: 6026 Cov.: 0 AF XY: 0.104 AC XY: 35465 AN XY: 341990

African (AFR) AF: 0.331 AC: 5858 AN: 17676

American (AMR) AF: 0.259 AC: 11300 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 732 AN: 20848

East Asian (EAS) AF: 0.307 AC: 11079 AN: 36052

South Asian (SAS) AF: 0.0659 AC: 4602 AN: 69788

European-Finnish (FIN) AF: 0.0624 AC: 3317 AN: 53126

Middle Eastern (MID) AF: 0.0925 AC: 382 AN: 4128

European-Non Finnish (NFE) AF: 0.0811 AC: 28337 AN: 349358

Other (OTH) AF: 0.119 AC: 3918 AN: 33026

GnomAD4 genome AF: 0.169 AC: 25112 AN: 149026 Hom.: 3140 Cov.: 32 AF XY: 0.168 AC XY: 12183 AN XY: 72660

African (AFR) AF: 0.329 AC: 13327 AN: 40526

American (AMR) AF: 0.221 AC: 3231 AN: 14622

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3462

East Asian (EAS) AF: 0.306 AC: 1375 AN: 4492

South Asian (SAS) AF: 0.0633 AC: 291 AN: 4598

European-Finnish (FIN) AF: 0.0669 AC: 707 AN: 10566

Middle Eastern (MID) AF: 0.0948 AC: 22 AN: 232

European-Non Finnish (NFE) AF: 0.0829 AC: 5604 AN: 67566

Other (OTH) AF: 0.164 AC: 336 AN: 2052

Alfa AF: 0.0999 Hom.: 365

Bravo AF: 0.196

Asia WGS AF: 0.165 AC: 563 AN: 3420

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0010
DANN	Benign	0.48
PhyloP100		-9.0

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: rs232230; hg19: chr2-89156948; COSMIC: COSV66419684;