NM_033377.2:c.227A>C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_033377.2(CGB1):​c.227A>C​(p.Asn76Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00092 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB1 NM_033377.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.27

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025533944).
• BP6: Variant 19-49035851-T-G is Benign according to our data. Variant chr19-49035851-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2380607.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGB1	NM_033377.2	c.227A>C	p.Asn76Thr	missense_variant	Exon 3 of 3	ENST00000301407.8	NP_203695.2
CGB1	NM_001382421.1	c.191A>C	p.Asn64Thr	missense_variant	Exon 3 of 3		NP_001369350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CGB1	ENST00000301407.8	c.227A>C	p.Asn76Thr	missense_variant	Exon 3 of 3	1	NM_033377.2	ENSP00000301407.6
ENSG00000267335	ENST00000591656.1	c.-28+675A>C		intron_variant	Intron 1 of 2	2		ENSP00000466140.1
ENSG00000267335	ENST00000604577.1	c.9+852A>C		intron_variant	Intron 1 of 2	1		ENSP00000474022.1
CGB1	ENST00000601167.1	c.191A>C	p.Asn64Thr	missense_variant	Exon 3 of 3	5		ENSP00000472896.2

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 33 AN: 146662 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000345

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000214 AC: 28 AN: 130716 Hom.: 0 AF XY: 0.000199 AC XY: 14 AN XY: 70296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000541

Gnomad SAS exome AF: 0.0000501

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000919 AC: 1254 AN: 1364216 Hom.: 0 Cov.: 30 AF XY: 0.000825 AC XY: 557 AN XY: 675178

Gnomad4 AFR exome AF: 0.000758

Gnomad4 AMR exome AF: 0.000350

Gnomad4 ASJ exome AF: 0.000164

Gnomad4 EAS exome AF: 0.000704

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.0000229

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000723

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000225 AC: 33 AN: 146782 Hom.: 0 Cov.: 26 AF XY: 0.000154 AC XY: 11 AN XY: 71452

Gnomad4 AFR AF: 0.0000771

Gnomad4 AMR AF: 0.000270

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000395

Gnomad4 SAS AF: 0.000221

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000345

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000961 Hom.: 0

ExAC AF: 0.000120 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 28, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.64
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-0.78	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	3.0	N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0070	B;.
Vest4		0.15
MutPred		0.59		Loss of stability (P = 0.0591);.;
MVP		0.67
MPC		1.2
ClinPred		0.014	T
GERP RS		0.68
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs544218520; hg19: chr19-49539108;