NM_033377.2:c.322T>C

Variant names:

• chr19-49035756-A-G
• rs535514659
• NM_033377.2:c.322T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_033377.2(CGB1):​c.322T>C​(p.Cys108Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000268 in 149,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB1 NM_033377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• Publications: 0 publications found

Genes affected

CGB1 (HGNC:16721): (chorionic gonadotropin subunit beta 1) The beta subunit of chorionic gonadotropin (CGB) is encoded by six highly homologous and structurally similar genes that are arranged in tandem and inverted pairs on chromosome 19q13.3, and contiguous with the luteinizing hormone beta (LHB) subunit gene. The CGB genes are primarily distinguished by differences in the 5' untranscribed region. This gene was originally thought to be one of the two pseudogenes (CGB1 and CGB2) of CGB subunit, however, detection of CGB1 and CGB2 transcripts in vivo, and their presence on the polysomes, suggested that these transcripts are translated. To date, a protein product corresponding to CGB1 has not been isolated. The deduced sequence of the hypothetical protein of 132 aa does not share any similarity with that of functional CGB subunits (PMID:8954017). However, a 155 aa protein, translated from a different frame, is about the same size, and shares 98% identity with other CGB subunits. [provided by RefSeq, Jul 2008]

ENSG00000267335 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033377.2. 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
	CGB1	NM_033377.2	MANE Select	c.322T>C	p.Cys108Arg	missense	Exon 3 of 3	NP_203695.2	A6NKQ9-2
	CGB1	NM_001382421.1		c.286T>C	p.Cys96Arg	missense	Exon 3 of 3	NP_001369350.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CGB1	ENST00000301407.8	TSL:1 MANE Select	c.322T>C	p.Cys108Arg	missense	Exon 3 of 3	ENSP00000301407.6	A6NKQ9-2
	ENSG00000267335	ENST00000591656.1	TSL:2	c.-28+770T>C		intron	N/A	ENSP00000466140.1	K7ELM3
	ENSG00000267335	ENST00000604577.1	TSL:1	c.9+947T>C		intron	N/A	ENSP00000474022.1	S4R385

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 4 AN: 149000 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000417 AC: 10 AN: 239940 AF XY: 0.0000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000213 AC: 31 AN: 1457842 Hom.: 0 Cov.: 34 AF XY: 0.0000262 AC XY: 19 AN XY: 725062

African (AFR) AF: 0.00 AC: 0 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110724

Other (OTH) AF: 0.0000831 AC: 5 AN: 60134

GnomAD4 genome AF: 0.0000268 AC: 4 AN: 149118 Hom.: 0 Cov.: 26 AF XY: 0.0000138 AC XY: 1 AN XY: 72700

African (AFR) AF: 0.00 AC: 0 AN: 39818

American (AMR) AF: 0.00 AC: 0 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67438

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000499 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.93
Eigen	Benign	0.0079
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.62	D
PhyloP100		3.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.97		Gain of MoRF binding (P = 0.0534)
MVP		0.84
MPC		3.2
ClinPred		0.66	D
GERP RS		1.8
gMVP		0.69
Mutation Taster		=88/12	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: rs535514659; hg19: chr19-49539013;