rs186163123

Variant names:

• chr2-44942323-C-T
• rs186163123
• NM_005413.4:c.219C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-44942323-C-T
• chr2-44942323-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005413.4(SIX3):​c.219C>T​(p.Pro73Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,593,348 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: SIX3 NM_005413.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13
• Publications: 0 publications found

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

ENSG00000225156 (HGNC:):

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-44942323-C-T is Benign according to our data. Variant chr2-44942323-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000989 (150/151694) while in subpopulation NFE AF = 0.00184 (125/67782). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005413.4. 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
	SIX3	NM_005413.4	MANE Select	c.219C>T	p.Pro73Pro	synonymous	Exon 1 of 2	NP_005404.1	O95343

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.219C>T	p.Pro73Pro	synonymous	Exon 1 of 2	ENSP00000260653.3	O95343
	ENSG00000225156	ENST00000760330.1		n.135+7947C>T		intron	N/A
	SIX3-AS1	ENST00000760560.1		n.389-1490G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000990 AC: 150 AN: 151582 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000809 AC: 176 AN: 217666 AF XY: 0.000919

Gnomad AFR exome AF: 0.000474

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000542

GnomAD4 exome AF: 0.00131 AC: 1888 AN: 1441654 Hom.: 2 Cov.: 33 AF XY: 0.00125 AC XY: 898 AN XY: 717162

African (AFR) AF: 0.000270 AC: 9 AN: 33354

American (AMR) AF: 0.000315 AC: 14 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39496

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00162 AC: 1795 AN: 1109740

Other (OTH) AF: 0.00108 AC: 65 AN: 59946

GnomAD4 genome AF: 0.000989 AC: 150 AN: 151694 Hom.: 0 Cov.: 31 AF XY: 0.000958 AC XY: 71 AN XY: 74128

African (AFR) AF: 0.000314 AC: 13 AN: 41462

American (AMR) AF: 0.000459 AC: 7 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 67782

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000940 Hom.: 0

Bravo AF: 0.000861

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Holoprosencephaly 2 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		1.1
Mutation Taster		=99/1	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: rs186163123; hg19: chr2-45169462;