19-49035851-T-C

Variant names:

• chr19-49035851-T-C
• rs544218520
• NM_033377.2:c.227A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033377.2(CGB1):​c.227A>G​(p.Asn76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N76T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB1 NM_033377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.227A>G	p.Asn76Ser	missense	Exon 3 of 3	NP_203695.2	A6NKQ9-2
	CGB1	NM_001382421.1		c.191A>G	p.Asn64Ser	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.227A>G	p.Asn76Ser	missense	Exon 3 of 3	ENSP00000301407.6	A6NKQ9-2
	ENSG00000267335	ENST00000591656.1	TSL:2	c.-28+675A>G		intron	N/A	ENSP00000466140.1	K7ELM3
	ENSG00000267335	ENST00000604577.1	TSL:1	c.9+852A>G		intron	N/A	ENSP00000474022.1	S4R385

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000220 AC: 3 AN: 1364444 Hom.: 0 Cov.: 30 AF XY: 0.00000296 AC XY: 2 AN XY: 675280

African (AFR) AF: 0.00 AC: 0 AN: 30352

American (AMR) AF: 0.00 AC: 0 AN: 37142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24348

East Asian (EAS) AF: 0.00 AC: 0 AN: 36928

South Asian (SAS) AF: 0.00 AC: 0 AN: 80776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3968

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1050446

Other (OTH) AF: 0.00 AC: 0 AN: 56738

GnomAD4 genome Cov.: 26

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.95
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.23	T
PhyloP100		2.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.26
Sift	Uncertain	0.014	D
Sift4G	Benign	0.090	T
Polyphen		0.33	B
Vest4		0.085
MutPred		0.62		Loss of stability (P = 0.075)
MVP		0.77
MPC		1.2
ClinPred		0.68	D
GERP RS		0.68
gMVP		0.099
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs544218520; hg19: chr19-49539108;