2-48962782-C-T

Variant names:

• chr2-48962782-C-T
• rs6166
• NM_000145.4:c.2039G>A
• FSHR p.Ser680Asn

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_000145.4(FSHR):c.2039G>A (p.Ser680Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.558 (AC=900,176) in the gnomAD database across 1,613,272 control chromosomes, including 252,236 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.661. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.57 (24652 hom., cov: 32)
  • Exomes 𝑓: 0.56 (227584 hom.)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0530
• Publications: 283 publications found

Genes affected

FSHR (HGNC:3969): (follicle stimulating hormone receptor) The protein encoded by this gene belongs to family 1 of G-protein coupled receptors. It is the receptor for follicle stimulating hormone and functions in gonad development. Mutations in this gene cause ovarian dysgenesis type 1, and also ovarian hyperstimulation syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

FSHR Gene-Disease associations (from GenCC):

• ovarian hyperstimulation syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• ovarian dysgenesis 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MIR548BAHG (HGNC:58158): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6607 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000145.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FSHR NM_000145.4	MANE Select	c.2039G>A p.Ser680Asn	missense	Exon 10 of 10	Prot: NP_000136.2
	FSHR NM_181446.3		c.1961G>A p.Ser654Asn	missense	Exon 9 of 9	Prot: NP_852111.2 UniProt:

FSHR NM_000145.4

MANE Select

HGVSc / HGVSpc.2039G>Ap.Ser680Asn

Exon rankExon 10 of 10

missense

Prot: NP_000136.2

FSHR NM_181446.3

HGVSc / HGVSpc.1961G>Ap.Ser654Asn

Exon rankExon 9 of 9

missense

Prot: NP_852111.2UniProt: P23945-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FSHR ENST00000406846.7	TSL:1MANE Select	c.2039G>A p.Ser680Asn	missense	Exon 10 of 10	Prot: ENSP00000384708.2 UniProt:
	FSHR ENST00000304421.8	TSL:1	c.1961G>A p.Ser654Asn	missense	Exon 9 of 9	Prot: ENSP00000306780.4 UniProt:
	MIR548BAHG ENST00000634588.1	TSL:5	n.492+16377C>T	intron	Intron 2 of 4	Prot:

FSHR ENST00000406846.7

TSL:1MANE Select

HGVSc / HGVSpc.2039G>Ap.Ser680Asn

Exon rankExon 10 of 10

missense

Prot: ENSP00000384708.2UniProt: P23945-1

FSHR ENST00000304421.8

TSL:1

HGVSc / HGVSpc.1961G>Ap.Ser654Asn

Exon rankExon 9 of 9

missense

Prot: ENSP00000306780.4UniProt: P23945-3

MIR548BAHG ENST00000634588.1

TSL:5

HGVSc / HGVSpn.492+16377C>T

Exon rankIntron 2 of 4

intron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.568	AC:86242	Hom:24645	AN:151908	Cov:32
GnomAD2 exomes	AF: 0.574	AC:144230	Hom:	AN:251060	Cov:
GnomAD4 exome	AF: 0.557	AC:813884	Hom:227584	AN:1461246	Cov:48
GnomAD4 genome	AF: 0.568	AC:86292	Hom:24652	AN:152026	Cov:32
TOPMed (Bravo)	AF: 0.574	AC:151916	Hom:43859	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.557	AC:416092	Hom:116077	AN:746658	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.577	AC:1352	Hom:396	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.691	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.557	AC:167	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.558	AC:7260	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.588	AC:2045	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.665	AC:4813	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.532	AC:1070	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.651	AC:79969	Hom:26084	AN:122806	Cov:
Turkish Variome	AF: 0.502	AC:3372	Hom:866	AN:6722	Cov:
UK10K	AF: 0.551	AC:4165	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.682	AC:6110	Hom:2082	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.532 *	5906	11106	0.542 *	9539	17594
BipEx(Bipolar disorder (including schizoaffective))	0.561	15932	28420	0.556	16027	28844
Epi25(Epilepsy)	0.566	23739	41958	0.566	37833	66888
SCHEMA(Schizophrenia)	0.577	96899	168016	0.572	160449	280736

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ovarian hyperstimulation syndrome (3)
-	-	2	not provided (2)
-	-	2	Ovarian dysgenesis 1 (2)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.7
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.29
DANN	Benign	0.18
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.0068	N
GPN-Star LLR	N/A	3.7
GPN-Star score	N/A	-0.13
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000060	T
MetaSVM	Benign	-0.92	T
Mutation Taster	N/A	99/1	polymorphism (auto)
PhyloP100	Benign	0.053
popEVE	Benign	-2.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.033
Sift	Benign	0.97	T
Sift4G	Benign	0.71	T
VESM-3B	Benign	-3.9

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs6166;

hg19: chr2-49189921;

COSMIC: COSV58619885;

COSMIC: COSV58619885;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar